recent developments in the synthesis of pyrido[1,2-a

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R. Khajuria et al. ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 X© Georg Thieme Verlag Stuttgart · New York2018, 50, 2131–2149reviewen

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Recent Developments in the Synthesis of Pyrido[1,2-a]benzimid-azolesRajni Khajuriaa,b ◊ Sk. Rasheedc,d ◊ Chhavi Khajuriae Kamal K. Kapoor*a Parthasarathi Das*c,d,f

a Department of Chemistry, University of Jammu, Jammu 180006, [email protected]

b Department of Chemistry and Chemical Sciences, Central University of Jammu, Jammu 181143, India

c Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, [email protected]

d Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Jammu 180001, India

e Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Indiaf Department of Applied Chemistry, Indian Institute of Technology (Indian School

of Mines), Dhanbad 826004, India

◊ These authors contributed equally to this work.

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Received: 03.01.2018Accepted after revision: 21.02.2018Published online: 24.04.2018DOI: 10.1055/s-0036-1589533; Art ID: ss-2018-e0009-r

Abstract Pyrido[1,2-a]benzimidazole is one of the most importantazaheterocyclic compounds consisting of three fused aromatic rings.Molecules containing this core have displayed a wide range of applica-tions in the field of medicinal chemistry. The synthesis of pyrido[1,2-a]benzimidazole and its derivatives has attracted organic chemists be-cause of its tremendous utility in interdisciplinary branches of chemis-try. In this context, this review discusses the main advances in the syn-thesis of pyrido[1,2-a]benzimidazoles via metal-mediated and metal-free reactions from 2000 to 2016.1 Introduction2 Synthetic Approaches to Pyrido[1,2-a]benzimidazoles2.1 Type I: Transition-Metal-Catalyzed Methods2.2 Type II: Metal-Free Approaches3 Conclusion

Key words azaheterocyclic compounds, pyrido[1,2-a]benzimidazoles,transition-metal mediated, metal-free reactions, nitrogen heterocycles

1 Introduction

Pyrido[1,2-a]benzimidazole is one of the most import-ant heterocyclic systems because of its occurrence as a syn-thon in various bioactive molecules and materials. This coreexhibits remarkable biological properties such as anti-malarial, anticancer, antiproliferative, antitumor, antifun-gal, antiviral, and antipyretic activities (Figure 1).1 Pyri-do[1,2-a]benzimidazole was initially prepared in the late1930s,2 but has received attention only during the past de-cade, when some of its derivatives were found to have phar-maceutical applications.3 Moreover, the difficulties associ-ated with the preparation of this heterocyclic system, oftencomprising of laborious and low-yielding methods, became

the point of concern for organic chemists.4 The importantbiological properties shown by pyrido[1,2-a]benzimidazoleand its derivatives have inspired organic chemists to devel-op simple and convenient synthetic methods. The reviewpresented here on synthetic strategies for pyrido[1,2-a]benzimidazoles is organized according to whether the re-action is metal-catalyzed (type I) or metal-free (type II).

Figure 1 Pyrido[1,2-a]benzimidazole based bioactive molecules

2 Synthetic Approaches to Pyrido[1,2-a]benzimidazoles

2.1 Type I: Transition-Metal-Catalyzed Methods

Transition-metal-catalyzed reactions have been studiedsince the very beginning of the past century and representa great success in organic chemistry along with the birthand growth of organometallic chemistry.5 Transition-metal-catalyzed coupling reactions, which were initiated in the1960s as a major topic in organometallic chemistry, have

antimalarial agent anticancer agent

N

NN

Me

I

antiproliferative agent

N

N

S

antitumor agent

N

NN

CN

NHN

antifungal agent

N

NH

O

CNH3C

F

F

antiviral agent

N

N

CN

NHN

F3C

N

N

CN

© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 2131–2149

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Biographical Sketches

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Rajni Khajuria received herM.Sc. (2010) from the Depart-ment of Chemistry, Universityof Jammu, India and M.Phil.(2012) at the same universityunder the guidance of Prof. Ka-mal K. Kapoor. She then workedon the synthesis of novel aza-

heterocyclic compounds as anti-microbial agents in the samelaboratory and obtained herPh.D. in 2016. Presently, sheworks as an assistant professoron contract basis in the Depart-ment of Chemistry and Chemi-cal Sciences, Central University

of Jammu. Her main research in-terests include the developmentof greener synthetic methods toaccess biologically activeheterocycles and coupling reac-tions for C–C and C–X bondformation.

Sk. Rasheed received his M.Sc.(2009) in organic chemistryfrom Osmania University, Hy-derabad, India and in 2010 hejoined the Indian Institute of In-tegrative Medicine (CSIR-IIIM),Jammu as a CSIR Junior Re-search Fellow. In 2011, he regis-

tered with the Academy ofScientific and Innovative Re-search (AcSIR) for a Ph.D. pro-gram under the supervision ofDr. Parthasarathi Das on the re-search topic ‘Transition-Metal-Catalyzed C–C and C–N BondFormation: Synthesis of Carba-

zoles and Aza-Fused Hetero-cycles’ and received his degreein 2017. Presently, he is workingas a senior research associate atGland Pharma Ltd., Hyderabad,India.

Chhavi Khajuria is an under-graduate student of integratedBSc. Honors in chemistry at the

Department of Chemistry, GuruNanak Dev University, Amritsar,India. She wishes to pursue her

career in synthetic and biologi-cal chemistry.

Kamal K. Kapoor received hisPh.D. (1996) from IIT, Kanpur,India. He joined the Universityof Jammu as lecturer in Decem-ber 1995, where he is professorat present. His research inter-ests include the synthesis ofnovel heterocyclic compounds

having significance in scaffoldhopping, biology, and materialscience. He was awarded DST-BOYSCAST and INSA Royal Soci-ety fellowships for visiting Japanand UK, respectively. He hasserved as lead scientist in DaburResearch Foundation, Sahib-

abad (UP) and Sphaera Pharma,IMT Manesar (Haryana), as advi-sory consultant to CuradevPharma Pvt Ltd, Noida, and alsoas adjunct professor at the Cen-tral University of Jammu.

Parthasarathi Das receivedhis Ph.D. (1999) from NCL Pune,India. After completing post-doctoral studies at RWTH-Aachen, Germany, Tohoku Uni-versity, Japan, and Harvard Uni-versity, USA, he returned toIndia to join Dr. Reddy’s Labora-tories Ltd. (2004) and worked in

the medicinal chemistry groupwith a research focus on varioustherapeutic areas (oncology,metabolic disorder, and anti-bacterial). In 2012, he shifted toacademia and joined the CSIR-Indian Institute of IntegrativeMedicine Jammu, India. Recent-ly, he moved to the Indian Insti-

tute of Technology (ISM)Dhanbad. His research interestsinclude medicinal chemistry,the development of new syn-thetic tools, and the synthesis ofbiologically active natural prod-ucts.


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made significant progress in the last half century andbecome one of the most efficient and direct strategies forcarbon–carbon bond formation.6 The extensive variationsand modifications of transition-metal-catalyzed couplingreactions have enabled wide applications in organic syn-thesis and have been regarded as the most reliable, accu-rate, and powerful tools in the chemist’s arsenal.7 Manynamed reactions have been assigned and are well knownnowadays, together with the development of novel chemi-cal reagents. The great success and significance of transi-tion-metal-catalyzed coupling reactions were highlightedby the 2010 Nobel Prize in chemistry.8

In 2003, Junjappa et al. reported a dexterous method forthe preparation of 1,2- and 2,3-substituted/annulated pyri-do[1,2-a]benzimidazoles via regioselective annulation of 2-methylbenzimidazole or 2-(cyanomethyl)benzimidazoledianions with α-oxo ketene dithioacetals involving [3+3]cyclocondensation (Scheme 1).9 The dianion derived from2-methylbenzimidazole undergoes 1,2-addition with α-oxoketene dithioacetals, followed by intramolecular cyclocon-densation in the presence of phosphoric acid to provide thecorresponding 1-(methylthio)-2,3-substituted pyrido[1,2-a]benzimidazoles. The dianion of 2-(cyanomethyl)benzim-idazole is involved in a one-pot 1,4-addition–eliminationand cyclocondensation with α-oxo ketene dithioacetals toform 4-cyano-3-(methylthio)-1(or 1,2)-substituted pyri-do[1,2-a]benzimidazoles.

Scheme 1 Regioselective synthesis of 1,2- and 2,3-substituted/annu-lated pyrido[1,2-a]benzimidazoles

In 2004, Maes et al. reported a tandem palladium-cata-lyzed Buchwald–Hartwig amination reaction for the syn-thesis of benzo and aza analogues of dipyrido[1,2-a:3′,2′-d]imidazole (Scheme 2).10 The regio- and chemoselectiveone-pot inter- and intramolecular Buchwald–Hartwig ami-nation of 2-chloro-3-iodopyridine with aminoazines/amino-diazines using Pd(BINAP)/Pd(XANTPHOS) catalysts in com-bination with an excess of Cs2CO3 base in toluene under re-flux conditions afforded the corresponding dipyrido[1,2-a:3′,2′-d]imidazole derivatives in excellent yields.

The catalytic cycle proposed for the tandem doublepalladium-catalyzed amination of 2-chloro-3-iodopyridinewith 2-aminopyridine (Scheme 3) starts with the oxidativeaddition of 2-chloro-3-iodopyridine to Pd(0), forming anorganopalladium(II) complex 3. Insertion of 2-aminopyri-dine into intermediate 3 generates another intermediate 4,

NH

NMe

NH

N CN

N

N

R2

SMe

N

N

MeS

R2

CN

MeS

SMe

O R2

BuLi (2 equiv), THF, 0 °C to rt

R1

R1

1.

2. H3PO4, heat

(1 equiv)

LDA (2 equiv), THF, 0 °C to rt

R1

R1 = H, R2 = Ph 70%R1 = H, R2 = Me 70%R1 = Me, R2 = Me 62%

R1 = H, R2 = Ph 76%R1 = H, R2 = Me 72%R1 = Me, R2 = Me 64% R1 = Me, R2 = Ph 74%

Scheme 2 Synthesis of benzo and aza analogues of dipyrido [1,2-a:3′,2′-d]imidazole

N Cl

I

+N NH2

NN N

N

NCs2CO3 (4 equiv)toluene, reflux,17 h

N

N

N

N N

N

N N

N

N N N

N

N

N N

N

N

N N

N

96% 98%

93% 82%94%

98%

(1 equiv) (1 equiv or 1.2 equiv)

Pd(OAc)2 BINAP 1 or XANTPHOS 2

6 examples82–98% yield

O

MeMe

PPh2 PPh2

2

PPh2

PPh2

1

Scheme 3 Plausible mechanism for the tandem double palladium-cat-alyzed synthesis of dipyrido[1,2-a:3′,2′-d]imidazole

N Cl

I

N NH2

N N

N

PdP

P

PdP

P

I

N

Cl

PdP

P

I

N

ClNH

N

PdP

PN

ClNH

N

N Cl

HN

N

HI

PdP

P

Cl

N

HN N

PdP

PN

NHN

Cl

PdP

PN

NN

PdP

P

Cl

N

NH

N

HN

N

amidine

3

4

5

6

7

7'

HCl


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which upon deprotonation followed by reductive elimina-tion gives N-(2-chloropyridin-3-yl)pyridine-2-amine (5).Then 5 undergoes oxidative addition to Pd(0) forming an-other organopalladium(II) complex 6. Coordination of thepyridine ring nitrogen with the metal center occurs, form-ing a palladacycle 7 over the competitive formation of palla-dium(II)–amine complex 7′. Deprotonation of 7 and subse-quent reductive elimination gives the final desired product,along with the regeneration of the palladium catalyst.

Two years later, the same group reported the regioselec-tive orthogonal (Pd- and Cu-catalyzed) or auto-tandem (Pd-catalyzed) inter- and intramolecular Buchwald–Hartwigamination reaction for the expedient synthesis of dipyri-do[1,2-a:2′,3′-d] imidazole and its benzo and aza analoguesby using 2,3-dibromopyridine and amino(di)azines as start-ing materials (Schemes 4 and 5).11 The orthogonal tandem-catalyzed amination is based on a chemoselective oxidativeaddition, which involves consecutive Pd-catalyzed intermo-lecular amination and Cu-catalyzed intramolecular amina-tion steps (Scheme 4).

Scheme 4 Orthogonal tandem Pd- and Cu-catalyzed amination of 2,3-dibromopyridine with amino(di)azines

In addition, an auto-tandem inter- and intramolecularPd-catalyzed amination by a simple alteration of the reactiontemperature was also presented. The auto-tandem Pd-cata-lyzed amination was performed at 140 °C (Scheme 5) and atrefluxing temperature. Double amination of 2,3-dibromo-pyridine at 140 °C occurred smoothly with 2-aminoisoquin-oline, 1-aminoquinoline and 3-aminopyridazine to give thecorresponding dipyrido[1,2-a:2′,3′-d]imidazoles, whereasthe same reaction of all amino(di)azines performed underreflux conditions gives only the respective intermediates, i.e.N-(3-bromopyridin-2-yl)azaheteroaryl amines.

In 2006, H. Ila and co-workers presented an efficientmethod for the synthesis of diversely substituted benzimid-azo[1,2-a]quinolines in high yields (Scheme 6).12 They de-scribed the Pd(PPh3)4-catalyzed Buchwald–Hartwig intra-molecular N-arylation of readily accessible 2-(2-bromoani-lino)quinolines, using K2CO3 as a base in DMF at 130–140 °C. The requisite starting materials, i.e. 2-(2-bromo-

anilino)quinolines, were in turn prepared from 2-(methyl-sulfonyl)quinolines and various 2-bromoanilines under re-flux conditions.13

Scheme 6 Pd(PPh3)4-catalyzed synthesis of benzimidazo[1,2-a]quinolines

A plausible mechanism for the formation of benzimid-azo[1,2-a]quinoline from 2-(2-bromoanilino)quinoline usingPd(PPh3)4 as a catalyst is presented in Scheme 7. Intermedi-ate 8, formed by the oxidative addition of Pd(0) to 2-(2-bro-moanilino)quinoline, undergoes an intramolecular nucleop-hilic attack at the basic quinoline nitrogen; this is followedby the elimination of HBr to give the six-membered pallada-cycle intermediate 9. Palladacycle 9, upon subsequent reduc-tive elimination and N–C bond formation steps, yields thecorresponding benzimidazo[1,2-a]quinoline.

One year later, the Maes group reported the applicationof their previously developed regioselective auto-tandem(Pd-catalyzed) and orthogonal-tandem (Pd- and Cu-cata-lyzed) protocols for the effective aminations of dihaloquin-olines with amino(benzo)(di)azines (Schemes 8 and 9).14

The synthesis of pyrido[2′,1′:2,3] imidazo[4,5-b]quinolineand its benzo and aza analogues was achieved viaPd(OAc)2–rac-BINAP/XANTPHOS-catalyzed amination of 2-chloro-3-iodoquinoline with various amino(ben-zo)(di)azines (Scheme 8). In the orthogonal-tandem amina-

N Br

Br

+N NH2

N

N N

N

Cs2CO3 (4 equiv)DME, 140 °C, 24–30 h

24 h, 80%24 h, 88%

30 h, 86%

24 h, 44%

(1 equiv) (1.2 equiv)

Pd2(dba)2 XANTPHOS, CuI N


N N

N

N

N

NN N

N

N N

N N

30 h, 76%N N

N

N

Scheme 5 Auto-tandem Pd-catalyzed inter- and intramolecular amina-tion of 2,3-dibromopyridine with amino(di)azines at 140 °C

N Br

Br

+N NH2

N

N N

N

Cs2CO3 (4 equiv)DME, 140 °C, 24 h

93% 76%


Pd2(dba)2 XANTPHOS N


NN

NN N

N

97%

N N

N

N

Br

NH

N

R3

R2R1

R4 Pd(PPh3)4 (10 mol%)


70%75%

82%

91% 93%

88%92%

(1 equiv)

DMF/K2CO3 130–140 °C, 12 h

N

NR4

R1 R2

R3

N

N

N

N

MeO

N

N Me

N

NMe

N

Ni-Pr

N

NMe Me

N

NMeO Me

Me

Representative examples


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tion, the Pd2(dba)3–XANTPHOS and CuI combination gavean easy access to various benzo and aza analogues of pyri-do[1′,2′:1,2]imidazo[4,5-b]quinoline using amino(benzo)(di)azines and 2,3-dibromoquinoline as starting materials(Scheme 9).

Scheme 8 Synthesis of pyrido[2′,1′:2,3]imidazo[4,5-b]quinoline and its benzo and aza analogues via Pd(OAc)2 auto-tandem amination

Subsequently, they reported that by controlling the re-action temperature of the Pd2(dba)3–XANTPHOS-catalyzedauto-tandem reaction, selective C-2 intermolecular amina-tion of 2,3-dibromoquinoline with amino(benzo)(di)azines

could be achieved to provide the corresponding N-(3-bromo-quinolin-2-yl)azaheteroaryl amines as the sole products ingood yields (Scheme 10).14

The Zhu group developed a novel strategy for the synthe-sis of pyrido[1,2-a]benzimidazoles through the direct intra-molecular aromatic C–H amination of N-aryl-2-aminopyri-dines, in which the pyridine moiety serves as a directinggroup as well as an intramolecular nucleophile (Scheme11).15 The reaction is co-catalyzed by Cu(OAc)2 andFe(NO3)3·9H2O in DMF under an O2 atmosphere to providegood to excellent yields of diversely substituted pyrido[1,2-a]benzimidazoles. The presence of electron-withdrawinggroups at any position of the pyridine ring and in the metaposition of aniline ring was found to be unfavorable for thereaction under the optimized reaction conditions.Fe(NO3)3·9H2O itself does not promote the reaction, but in-creases the yield of the reaction significantly due to its abilityto facilitate the formation of more electrophilic Cu(III) spe-cies, which readily undergo the SEAr (electrophilic aromaticsubstitution) process. Pivalic acid is used as an additive forthis reaction to improve the yields of the final products.

The following mechanism was proposed by Zhu et al. forthe Cu(OAc)2–Fe(NO3)3·9H2O co-catalyzed preparation ofpyrido[1,2-a]benzimidazole from N-phenyl-2-aminopyri-dine (Scheme 12).15 In the absence of Fe(III) salt, the Cu(II)salt forms intermediate 11 from the initially formed Cu(II)adduct 10 through electrophilic aromatic substitution, fol-lowed by reversible protonation. In the presence of oxygen,intermediate 12 is converted into a more reactive Cu(III) in-termediate 13 through oxidation; upon subsequent reduc-tive elimination, the requisite product is produced alongwith the formation of Cu(I). In the presence of Fe(III) salt,the initially formed adduct 10 is oxidized to a more electro-philic Cu(III) intermediate 14. Then 14 undergoes electro-philic aromatic substitution to generate intermediate 13through the formation of the six-membered transition state15. Reductive elimination takes place very quickly, beforereversible protonation, to yield the desired product. Theformed Cu(I) is oxidized into Cu(II) in the presence of O2,thus completing the catalytic cycle.

In 2010, Maes and co-workers reported further studiesof the scope of their well-established methodology of auto-tandem and orthogonal-tandem double aminations of diha-lopyridines, i.e. 2-chloro-3-iodopyridine and 2,3-dibromo-pyridine, with unexplored benzodiazinamines, i.e. phthala-zin-1-amine, quinoxalin-2-amine and quinazolin-4-amineas coupling partners (Schemes 13 and 14).16 The requisitebenzodiazinamines were prepared by using the literaturemethod of Hara and van der Plas.17 They observed that theirpreviously developed auto-tandem double amination pro-tocol for the coupling of 2-chloro-3-iodopyridine could notbe generally applied for benzodiazinamines, whereas theorthogonal-tandem double amination protocol for the cou-

Scheme 7 Pd(PPh3)4-catalyzed mechanism for the formation of ben-zimidazo[1,2-a]quinoline from 2-(2-bromoanilino)quinoline

PdLn

NH

N

Br LnPd

N

N

– HBrnucleophilic

attack

LnPd(0)

NH

NBr

reductive elimination

oxidativeaddition

K2CO3

8 9

N

N

N Cl

I

+N NH2

N

N N

N

NCs2CO3 (4 equiv)toluene, reflux, 17 h

N N

N

N N

N

N N

N

N N N

N

N

N N

N

96% 97% 98%

93% 81%

Pd(OAc)2 rac BINAP or XANTPHOS

(1 equiv) (1.2 equiv) 5 examples81–98% yield

Scheme 9 Synthesis of pyrido[1′,2′:1,2]imidazo[4,5-b]quinoline and its benzo and aza analogues via Pd2(dba)3-CuI orthogonal-tandem ami-nation

N Br

Br+

N NH2

NN

N

N

NCs2CO3 (4 equiv)DME, 140 °C, 24 h

N

N

N N

N

N

N

N

N

N

N

N

N

N

N

N

N

80% 85% 90%

70%14%

Pd2(dba)3 XANTPHOS, CuI



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pling of 2,3-dibromopyridine with benzodiazinamines re-vealed unexpected Smiles rearrangement at high tempera-ture. To prevent this undesired rearrangement step, therac,trans-cyclohexane-1,2-diamine ligand was used for thecopper catalyst to achieve the intermolecular and intra-molecular reactions for ring closure in a sequential manner.

The auto-tandem Pd(OAc)2–XANTPHOS-catalyzed dou-ble amination of 2-chloro-3-iodopyridine with benzodi-azinamine in refluxing toluene gave the desired pyri-do[3′,2′:4,5]imidazo [2,1-a]phthalazine in 80% yield(Scheme 13). Applying the same reaction conditions tophthalazin-1-amine and quinoxalin-2-amine did not givethe desired products. Instead, the reactions stopped at theintermolecular amination step, with no further intramolec-ular C–N bond formation. However, the synthesis of pyri-

do[3′,2′:4,5]imidazo[1,2-a]quinoxaline was successfullyachieved under the optimized auto-tandem double amina-tion reaction conditions by simply replacing toluene withDME as solvent under reflux conditions (Scheme 13). Forthe coupling of 2-chloro-3-iodopyridine with quinazolin-4-amine, a one-pot approach was developed consisting of aPd(OAc)2–XANTPHOS-catalyzed intermolecular aminationstep, followed by the addition of CuI in combination withthe rac,trans-cyclohexane-1,2-diamine ligand in a ratio of

Scheme 10 Temperature-dependent Pd2(dba)3–XANTPHOS-catalyzed auto-tandem amination of 2,3-dibromoquinoline with amino(benzo)(di)azines

N Br

Br

+N NH2

N

Cs2CO3 (4 equiv), DME

Pd2(dba)3 (1 mol%)XANTPHOS (2.2 mol%)


140 °C, 24 hreflux, 7 h

N

N

N

NN NH

BrN

N5 examples79–87% yield


N

N

N

N

N

N

N

N

N

N

N

N

N

N

15% 66%

35% 72%

N NH

BrN

N NH

BrN

N NH

BrN

N NH

Br

NN

N NH

Br NN

85%86%

87%

79% 84%

Scheme 11 Synthesis of diversely substituted pyrido[1,2-a]benzimid-azoles via Cu(OAc)2–Fe(NO3)3·9H2O co-catalyzed intramolecular C–H amination of N-aryl-2-aminopyridines

N

N

Me30 h, 81%

N

N

t-Bu36 h, 84%

N

N

Br62 h, 68%

N

N

Me

NH

NN

N

N

N

28 h, 82%

ArAr

R R

Me

Cu(OAc)2 (20 mol%)Fe(NO3)3·9H2O (10 mol%)

PivOH (5 equiv), O2 DMF, 130 °C, 5–70 h

(1 equiv) 21 examples24–96% yield

N

N F

16 h, 74% 46 h, 24%

N

N

70 h, 77%

N

N

23 h, 96%


Scheme 12 Mechanism proposed for the Cu(OAc)2-catalyzed intra-molecular C–H amination of N-phenyl-2-aminopyridine, with and with-out Fe(III) salt

H

N

NH

N

N

Cu+

N

N

Cu

N

N

CuOCOR

II

N

N

CuOCOR

N

N

N

N

CuO

III

R

O

N

N

Cu+

O O

R

H

FeIIIFeII

CuI CuII

– H2O

O2, H+

Cu(OCOR)2

– RCOOH RCOOH

– RCOOH RCOOH

Fe(NO3)3·9H2O

– H+

O2 + H+ H2O

O2 + H+ H2O

11

12

10

13

14

15

withoutFe(NO3)3·9H2O

RCOO–


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1:2, upon completion of the first amination, to access thedesired pyrido[3′,2′:4,5]imidazo[1,2-c]quinazoline (Scheme13). The one-pot method was also developed for the cou-pling of 2,3-dibromopyridine with benzodiazinamines, byreplacing Pd(OAc)2 with Pd2(dba)3 as a catalyst for ortho-gonal-tandem double amination (Scheme 14).

Scheme 14 Orthogonal-tandem double amination of 2,3-dibromo-pyridine with benzodiazinamines

One year later, the same group investigated the role ofan acid additive in the synthesis of diverse pyrido[1,2-a]benzimidazoles by direct Cu(OAc)2·H2O-catalyzed amina-tion of N-arylpyridin-2-amines in DMSO in the presence ofO2 at 120 °C (Scheme 15).18 They studied the influence ofthe structure of the acid additive and the result showedthat carboxylic acids such as acetic acid, pivalic acid, butyricacid, benzoic acid, and 3,4,5-trifluorobenzoic acid (TFBA)produced the desired products in good efficiency. Non-car-boxylic acids such as HCl were also found useful when usedin catalytic amounts. Among the various acid additivesscreened, 3,4,5-trifluorobenzoic acid was clearly found tobe a superior additive and this acid also provided a fasterreaction and complete conversion of the starting materialswhen used in an equimolar amount relative to the catalyst.

Scheme 15 Cu(OAc)2·H2O–TFBA-catalyzed synthesis of diversely sub-stituted pyrido[1,2-a]benzimidazoles

The mechanism proceeding via a Cu(II)/Cu(0) catalyticcycle was proposed in accordance with their findings andcontrol experiments (Scheme 16).18 The first step is the co-ordination of CuII(OCOR)2 with N-phenylpyridin-2-amine,leading to the formation of intermediate 17, followed by in-tramolecular nucleophilic attack of its amidine nitrogen onthe activated phenyl ring to give the σ-alkyl–Cu(II) interme-diate 18. Subsequent β-hydride elimination of 18 gives thecorresponding product and RCO2Cu(II)H. Reductive elimina-tion of RCOOH from RCO2Cu(II)H yields Cu(0), which is re-oxidized to Cu(II)(OCOR)2 with RCOOH in the presence ofO2, thus completing one catalytic cycle.

Subsequently, Wu et al. developed a simple method forthe expeditious synthesis of diversely substituted pyri-do[1,2-a]benzimidazoles through a CuI–1,10-Phen-cata-lyzed inter- and intramolecular C–N coupling cascade pro-cess using haloanilines and halopyridines as the couplingpartners in xylene at 120 °C (Scheme 17 and Scheme 18).19

Various substituted haloanilines and halopyridines bearingelectron-donating and electron-withdrawing substituents

Scheme 13 Auto-tandem and orthogonal-tandem double aminations of 2-chloro-3-iodopyridine with benzodiazinamines

N Cl

I

N N

N

N

rac,trans-cyclohexane-1,2-diamine

(1 equiv)

NN

NH2

(1.2 equiv)

Pd(OAc)2 (4 mol%)XANTPHOS (4.4 mol%)Cs2CO3 (4 equiv)toluene, reflux, 17 h

80%

N

N

H2N

(1.2 equiv)

Pd(OAc)2 (4 mol%)XANTPHOS (4.4 mol%)

Cs2CO3 (4 equiv)DME, reflux, 17 h

N N

N

N

82%

N

N

Pd(OAc)2 (4 mol%)XANTPHOS (4.4 mol%)Cs2CO3 (4 equiv)DME, reflux, 17 h

NH2

(1.2 equiv)

CuI (10 mol%)ligand 16 (20 mol%)reflux, 8 h

N N

N

N85%

NH2

NH2

16

N Br

Br

(1 equiv)

N

Pd2(dba)3 (4 mol%)XANTPHOS (4.4 mol%)

Cs2CO3 (4 equiv),DME, reflux, 17 h

NH2

(1.2 equiv)

CuI (10 mol%)ligand 20 (20 mol%)reflux, 8 h

+ N N N

N N


N N

N

N

93%N N

NN

65%

N

N

N

N99%

N

NH

Ar

DMSO, O2

120 °C, 24 h 11 examples55–98% yield

(1 equiv)

Cu(OAc)2·H2OTFBA

ArN

N

N

N

92%N

N

75%

F

N

N

98%

F

N

N

60%

MeO

N

N

59%OMe

N

NCl

78%

N

NEtO2C

57%

N

NF3C

80%



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were well tolerated under the optimized reaction condi-tions to afford the corresponding pyrido[1,2-a]benzimidaz-oles in good to excellent yields.

Scheme 17 CuI–1,10-Phen-catalyzed coupling of various substituted 2-haloanilines with 2-iodopyridine

They have proposed the following plausible reactionpathway for the CuI–1,10-Phen catalyzed inter- and intra-molecular amination of 2-iodopyridine with haloanilines(Scheme 19). The 2-haloaniline couples intermolecularlywith 2-iodopyridine via an Ullmann-type C–N bond forma-tion, due to the electron-deficient nature of the pyridinering, to give intermediate 19. Subsequent isomerization of

intermediate 19 into 20 followed by intramolecular Ull-mann-type C–N coupling leads to the formation of the de-sired product, as shown in Scheme 19.

Scheme 19 Proposed mechanism for the CuI–1,10-Phen-catalyzed pyrido[1,2-a]benzimidazole synthesis

In 2012, Fossey and co-authors reported a Cu(OTf)2-catalyzed intramolecular C–H bond amination reaction ofpurine and its derivatives, by employing PhI(OAc)2 as anoxidant in a 1:1 mixture of acetic acid and acetic anhydrideas a solvent, for the efficient synthesis of purine-fused poly-cyclic compounds (Scheme 20).20 This was the first reporton the utility of intramolecular C–H activation/aminationreaction protocols for the synthesis of purine nucleosides,which offers an easy alternative access to many usefulmulti-fused ring purine heterocyclic compounds.

Scheme 20 Cu(OTf)2-catalyzed synthesis of multi-fused ring purine heterocyclic compounds

The mechanism for the Cu(OTf)2-assisted intramolecu-lar C–H bond activation and amination of 6-anilinopurinebased substrates is outlined in Scheme 21. Oxidative addi-tion of substrate 21 to Cu(OTf)2 yields intermediate 22,which undergoes an electrophilic substitution process toform Cu(II) intermediate 23. The final step is the reductiveelimination of 23 to give the desired product, along withthe regeneration of Cu(OTf)2 to complete the Cu(II)/Cu(0)catalytic cycle.

Scheme 16 Plausible mechanism for the intramolecular C–H amina-tion of N-phenylpyridin-2-amine

NH

NCuII(OCOR)2

NH

NCu OCOR

ROCO

N

N

CuH

OCOR

H

RCO2CuH +Cu(0)– RCOOH

18

– RCOOH

N

N

2 RCOOH+

1/2 O2

H2O 17

NH2

X

X = Br, I

+N

I

Cs2CO3 (3 equiv), N2

xylene, 120 °C, 12–24 h

N

N

Ar1Ar1


CuI (2 mol%)1,10-Phen (4 mol%)

N

N

X = I 90%X = Br 77%

N

N

X = I 84%X = Br 53%

Me N

N

X = I 85%X = Br 64%

Cl N

N

X = I 91%X = Br 67%

Br

N

N

X = I 89%

Cl

N

N

X = I 39%

Me

MeN

N

X = Br 93%

MeOC N

N

X = Br 73%F

N N8 examples39–93% yield 1,10-Phen

Scheme 18 CuI–1,10-Phen-catalyzed coupling of 2-bromoaniline with various substituted 2-halopyridines

Me

NH2

Br

X= Br, I

+N

X

Cs2CO3 (3 equiv), N2

xylene, 120 °C, 24 h

N

N


CuI (2 mol%)1,10-Phen (4 mol%)

N

N

X = I 77%X = Br 58%

N

N

X = I 69%X = Br 61%

N

N

X = Br 55%

N

N

X = Br 53%

N

N

X = Br 50%

N

N

X = Br 25%

N

N

X = Br 53%

N

N

X = Br 61%


Ar2Ar2

Br

Me

OMeClMeMe

NH2

XX = Br, I

+ N

I

N

N

HN

XN

N

XHN

intermolecularUllmann-typeC–N coupling

intramolecularUllmann-typeC–N coupling

19 20

N

N N

N

NH

R

ArN

N

N

N

N

R

Ar

AcOH/Ac2O, 80 °C, 2 h

N

N

N

N

N

nBu

N

N

N

N

N

N

N

N

N

N

R

80% 85%

92%

R = O

OAcOAc

AcOEtO2C

N

N

N

N

N

R 88%

Cu(OTf)2 (8 mol%)PhI(OAc)2 (1.5 equiv)

(1 equiv)16 examples40–92% yield

N

N

N

N

N

84%

N

N

N

N

N

R

Cl

85%



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Scheme 21 Plausible mechanism for Cu(OTf)2-catalyzed intramolecu-lar C–H bond activation and amination of 6-anilinopurine-based sub-strates

In 2015, Das et al. described a ligand-free Cu(II)-cata-lyzed, inter/intramolecular C–N bond formation for thesynthesis of various benzimidazole-fused heteroaromaticcompounds (Scheme 22).21 The robustness of this methodwas demonstrated by the synthesis of a series of benzimid-azole-fused heterocycles, e.g., pyrido[1,2-a]benzimidazole,benzimidazo[1,2-a]quinolines, benzimidazo[1,2-a]pyra-zine, directly from 2-aminoheteroarenes and 2-iodoaryl-boronic acids in one pot. The novel cascade protocol for C–Nbond formation represents a distinctive example of a sole com-bination of Chan–Lam- and Ullmann-type coupling reactions.

The following plausible catalytic cycle was proposed forthe formation of pyrido[1,2-a]benzimidazole as shown inScheme 23. In the Chan–Lam type of coupling, the first stepis the rapid coordination of the Cu(II) complex with 2-aminopyridine, forming 24, which subsequently enters intoa transmetalation step with 2-iodophenylboronic acid to af-ford complex 25. Then Cu(II) complex 25 undergoes air oxi-dation to provide the higher oxidation Cu(III) complex 26,facilitating the smooth reductive elimination to furnish N-arylated product 27 (intermediate I). In the Ullmann-typecoupling, the first step involves the smooth coordination of27 with Cu(I) to form complex 28, which upon intramolec-ular oxidative addition with aryl iodide furnishes complex29, which subsequently converts into complex 30. As far asthe oxidation state of copper is concerned, these types ofreactions are supposed to proceed via Cu(I) and Cu(III) in-termediates. Thus, Cu(III) complex 30, on smooth reductiveelimination, furnishes the final cyclized product with con-current formation of Cu(I). Finally, Cu(II) is generated byaerial oxidation to complete the catalytic cycle.

N

N N

N

NH

R

R = alkyl, aryl, sugar

HN

N N

N

N

R21

N

N N

N

N

R

CuTfO

II

N

N N

N

N

R

CuII

LnCu(0)

Cu(OTf)2

TfOH

TfOH

PhI(OAc)2

22

23N

N N

N

R

N

Scheme 23 Mechanism proposed to explain the Cu(II)-catalyzed Chan–Lam coupling followed by Ullmann-type coupling of 2-aminopyridine with 2-iodophenylboronic acid to access pyrido[1,2-a]benzimidazole

B(OH)2

AcO B(OH)2AcOH

Cu(II)HN

OAc

O2

N NH2

Cu(II)(OAc)2

N

N

HN

I

Cu(II)HN

N

CuHN

NAcOH

H2OAcO (III)

Cu(I)OAc

N

N

ICu(I)

N

N

CuI

(III)

N

N

Cu

OAc

(III)

Cu(I)OAc

AcOH

AcOH

HI

NN

I

I

I

Chan–Lam type Ullmann-type

AcOH

H2O

O2

24

25

26

28

29

30

27

Scheme 22 Benzimidazole-fused heteroaromatics preparation via Cu(II)-catalyzed consecutive Chan–Lam- and Ullmann-type coupling reactions

N

N

NN

N

OMe

N

N

Cl

F

N

N

Cl

N

N

N NH2

+

I

(HO)2B Cs2CO3 ( 3 equiv)DMF, 120 °C, 24 h

75%

73% 80%

N

N

O

O

76%

N

NN

NN

Et 70%

N

N

OMeMe

86%MeO

Cu(OAc)2 (20 mol%)Het Ar

ArHet


N

N

OMe 88% 91%



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2.2 Type II: Metal-Free Approaches

Nevertheless, transition-metal-catalyzed coupling reac-tions are still limited in applications and confront challeng-es to some extent, owing to the innate drawbacks of thecatalytic systems. First, most of the transition-metal cata-lysts are normally very expensive22 and the supporting li-gands are usually even more expensive and sometimes dif-ficult to prepare. Second, most of the transition metals aretoxic to different extents, and removal of trace amounts oftransition-metal residues from the desired products is quitecostly and challenging, while crucial, especially in the phar-maceutical industry.23 Third, many transition-metal cata-lysts are usually sensitive to oxygen (O2) and moisture;thus, very strict manipulation is indispensable. Fourth, inmany cases, special additives and co-catalysts are also criti-cal to promote the efficiency and selectivity of transforma-tions.24 Last but not least, the large consumption of transi-tion metals does not indeed meet the requirement of sus-tainable development.25 Obviously, alternative pathways toconstruct C–C bonds under transition-metal-free condi-tions to fulfill the classic transition-metal-catalyzed cou-pling reactions are highly appealing. Thus, studies on tran-sition-metal-free coupling reactions are of great signifi-cance to provide a better understanding of how thereactions work with or without transition metals.

In 2009, the Yan group reported a one-pot, four-compo-nent method to afford diversely substituted pyrido[1,2-a]benzimidazoles, by employing aromatic aldehydes, malo-nonitrile, chloroacetonitrile, and pyridine or 3-picoline asstarting materials in refluxing acetonitrile (Scheme 24).26 Alibrary of pyrido[1,2-a]benzimidazole derivatives with broadsubstrate scope was synthesized in moderate to good yields.

The postulated mechanism (Scheme 25) begins with theformation of two reaction intermediates: the N-cyano-methylpyridinium salt 31, formed by the addition of chloro-acetonitrile to pyridine, and the benzylidenemalononitrile,formed by the pyridine-promoted Knoevenagel condensa-tion of malononitrile with benzaldehyde. In the secondstep, the pyridinium ylide 32, formed by the pyridine-as-sisted deprotonation of the N-cyanomethylpyridinium in-termediate 31, undergoes Michael addition with ben-zylidenemalononitrile to give an activated cyclopropanederivative 33. Upon subsequent deprotonation and ring-opening, 33 yields an allylic carbanionic intermediate 34,which reacts with the second molecule of benzylidene-malononitrile to form a cyano-stabilized carbanionic inter-mediate 35. The intramolecular nucleophilic addition ofcarbanion 35 to one of its cyano groups affords a fully sub-stituted six-membered cyclic intermediate 36. The substi-tution of one cyano group in intermediate 36 by pyridineoccurs to form another pyridinium ion 37. Pyridinium ion37 experiences an intramolecular attack of an amino groupon the ortho positive center of pyridine to form a cyclic pyr-idine derivative 38, from which one molecule of hydrogencyanide and two hydrogen atoms are eliminated to form thedesired pyrido[1,2-a]benzimidazole. In this mechanism,pyridine plays a multifaceted role, by acting as a tertiaryamine to yield pyridinium cation, as a base to form the car-banion intermediate and as a nucleophilic reagent.

In 2011, the Kutsumura group reported a versatilemethod for the synthesis of pyrido[1,2-a]benzimidazolesvia intramolecular dehydrogenative C–N coupling between

Scheme 24 One-pot, four-component method of preparation of poly-substituted pyrido[1,2-a]benzimidazoles

ArCHO CNNC

N

RN

N

R

CNCN

ArAr

R = H, Me

MeCN reflux, 6–24 h

CNCl

(2 equiv)(2 equiv) (1 equiv)

(1 equiv) 21 examples20–51% yield

N

N

CNCN N

N

CNCN

Me

Me

N

N

CNCN

BrBr

35% 20% 26%

+

N

N

CNCN

i-Pr

i-Pr

51%

N

N

CNCN

Cl

Cl

29%

Me N

N

CNCN

33%

Me

OMe

OMe


Scheme 25 Proposed mechanism for the catalyst-free synthesis of pyrido[1,2-a]benzimidazole

N

CNCl

– Cl N

CN

N

CN

Ph CN

CN

N

CNPh

NCCN

Ph

CN

CN

NC

Ph

CN

CN

NC

Ph

CN

CNNC

Ph CN

CN

C

CNCN

NC CN

Ph

PhN

CN

CN

Ph

Ph

N

NC

NC

N

CN

CN

Ph

Ph

N

NC

N

CNCN

PhN

N

NC Ph

CNCN

PhN

N

Ph

– HCN

– 2H

94

31

32

33

34

35

3637

38

– HPy

Py

– HPy

Py


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aryl C–H and N–H bonds of N-pyridin-2-ylanilines by usinghypervalent iodine reagents under mild reaction conditions(Scheme 26).27

The synthesis of pyrido[1,2-a]benzimidazoles in moder-ate to excellent yields via photo-stimulated cyclization of 2-(2-halophenylamino)pyridines in liquid ammonia and inthe presence of potassium tert-butoxide was reported byRossi and co-workers (Scheme 27).28 The reaction proce-dure involves the photo-stimulated SRN1 mediated C–Nbond formation in 2-(2-halophenylamino)pyridines. Vari-ous substituents were well tolerated on both the phenyland pyridine rings of the starting materials.

Scheme 26 Hypervalent iodine-assisted intramolecular dehydrogena-tive C–N coupling reactions of N-pyridin-2-ylanilines

The mechanism proposed for the photo-stimulatedcyclization of 2-(2-halophenylamino)pyridine is shown inScheme 28. The first step involves the generation of the rad-ical dianion 39 of the substrate by a photo-induced electrontransfer (ET) reaction. This radical dianion 39 upon frag-mentation yields the distonic radical anion 40 and thehalide anion, followed by the cyclization of the resonancedistonic radical anion 40 to give the conjugated radicalanion 41. Finally, an electron transfer from radical anion 41

to the anion of 2-(2-halophenylamino)pyridine leads to theformation of the final product, along with the intermediate39, to continue the propagation cycle.

Scheme 28 Photo-stimulated SRN1 cyclization of 2-(2-halophenyl-amino)pyridine

In 2013, a hypervalent iodine(III)-catalyzed C–H cyclo-amination reaction of N-aryl-2-aminopyridines was report-ed by Zhu et al. for the easy and efficient synthesis of vari-ous pyrido[1,2-a]benzimidazoles in good to excellent yields(Scheme 29).29 The hypervalent iodine(III) reagentphenyliodine diacetate (PIDA) was generated in situ from acatalytic amount of iodobenzene and a stoichiometricamount of peracetic acid. Various electron-donating andelectron-withdrawing groups were well tolerated under theoptimized reaction conditions to provide more diversifiedpyrido[1,2-a]benzimidazole derivatives.

Scheme 29 PIDA-catalyzed synthesis of pyrido[1,2-a]benzimidazole derivatives

The authors proposed the followed reaction pathway(Scheme 30) for the C–H cycloamination reaction of N-phenyl-2-aminopyridine catalyzed by an in situ generatedhypervalent iodine(III) reagent. The reaction starts with theformation of phenyliodine diacetate (PIDA) by the oxidationof iodobenzene with peracetic acid in the presence of acetic

N NH

X

R1

N

N X

R1

N

N

N

N

Me

N

N N

(1.0 equiv)

{A}

{B}

{C}3 examples

{A}: 6 h, 33% {B}: 2 h, 52%{C}: 6 h, 30%

{A}: 4 h, 62%{B}: 2 h, 73%{C}: 4 h, 44%

{A}: 28 h, 65%{B}: 4 h, 74%{C}: 24 h, 44%

PhI(OCOCF3)2 (2.0 equiv)CH2Cl2, 0 °C to rt

PhI(OH)OTs (1.1 equiv)MeCN, 0 °C to rt

PhI=NTs (1.1 equiv)Cu(OTf)2 (5 mol%)

CH2Cl2, –40 to 0 °C

Scheme 27 Photo-stimulated cyclization of 2-(2-halophenyl amino)-pyridines to afford the corresponding pyrido[1,2-a]benzimidazole deriv-atives

NH

YN

X

hν,

NH3(l), t-BuOK

N

N YAr1 Ar2

1–3 h

N

N

N

N

N

N

N

N

N

N

93% 62%

Me

F3C

79%

Me94%

Me

94%

(1 equiv)

Ar2

Ar1


X = Cl, BrY = CH, N

N

N

F

83%


NH

YN

XET

NY

NX

NY

N

N N

Y

NY

N

N

N Y

N

N Y+

39 40

4041

ET

NY

NX

39

– X

NH

YN

X

40

N

N

t-Bu

94%

N

N

F

94%N

N78%

N

N

HFIP, 25 °C, 1.5 h

PhI (10 mol%)

NH

NN

N

AcOOH (1.05 equiv)

N

N 91%

R1

R1

TMS

93%

R2

R2


N

N

Me85%

N

N

CO2Et

N

NF3C

67% 93%



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acid, followed by nucleophilic substitution of the anilinenitrogen of N-phenyl-2-aminopyridine on the iodine(III)center in PIDA to form intermediate 42, bearing an electro-philic N-iodo moiety. Subsequent nucleophilic attack fromthe pyridine nitrogen onto the aniline ring produces inter-mediate 43 along with the simultaneous release of PhI andacetate ion. The released PhI enters the catalytic cycle againupon its reoxidation by peracetic acid, which is used as astoichiometric oxidant. In the final step, the deprotonativerearomatization of intermediate 43 takes place, leading tothe formation of the desired final product, along with thegeneration of one molecule each of acetic acid and water asbyproducts.

Scheme 30 Mechanism for the PIDA-catalyzed C–H cycloamination reaction of N-phenyl-2-aminopyridine

Subsequently, the same group developed another mildand highly efficient, metal-free method for the oxidative,tandem demethylative C–H cycloamination of N-benzyl-2-aminopyridines using PhI(OPiv)2 as a stoichiometric oxi-dant to afford the corresponding pyrido[1,2-a]benzimidaz-oles in high yields (Scheme 31).30 This process involvesPhI(OPiv)2-mediated tandem C–C bond activation andintramolecular C–N bond formation steps.

The mechanism proposed for this transformation(Scheme 32) begins with the coordination of PhI(OPiv)2with N-benzyl-2-aminopyridine, leading to the formationof an electrophilic N-iodo species 44, which undergoes ipsoSEAr on the phenyl ring to furnish the delocalized carboca-tion 45 (Wheland intermediate). C–C bond cleavage in 45occurs upon its nucleophilic addition by HFIP at the benzyl-ic carbon, giving intermediate 46, which upon reaction witha second equivalent of PhI(OPiv)2 produces the active com-plex 47. A second nucleophilic addition by HFIP to 47 re-sults in C–N bond cleavage to give an activated electrophiliciodo species 48, along with the release of a methylenegroup in the form of an acetal. Electrophilic annulation onthe pyridine nitrogen of 48 forms intermediate 49, which isdeprotonated to the corresponding pyrido[1,2-a]benzimid-azole in the final step.

Scheme 32 Proposed reaction mechanism for the PhI(OPiv)2-promot-ed C–H cycloamination of N-benzyl-2-aminopyridine

In 2014, Antonchick et al. reported a metal-free annula-tion reaction between various substituted 2-aminopyri-dines/2-aminoquinolines and arenes to get an easy accessto diversified pyrido[1,2-a]benzimidazoles (Scheme 33)and quinolino[1,2-a]benzimidazoles (Scheme 34) undermild reaction conditions.31

A plausible mechanism for the formation of pyrido[1,2-a]benzimidazole is outlined in Scheme 35. It begins with aligand exchange between 2-aminopyridine and PhI(OAc)2to form intermediate 50, followed by nucleophilic attack ofp-xylene, forming N-arylated 2-aminopyridine 51. Sub-sequent oxidation of 51 with a second equivalent ofPhI(OAc)2 and nucleophilic attack of the pyridine nitrogenon xylene produces another intermediate 53, which uponrearomatization gives the final annulated product.

To be highlighted in this report is the in situ synthesis ofbenzylic amine 56 via an unprecedented participation ofthe methyl group of methylarene as a traceless, non-chelat-

NH

N

N

N

N

N

IOAcPh

PhI + AcOOH + AcOH

PhI(OAc)2

AcOH

N

N

H

PhI + AcO

H43

42

Scheme 31 PhI(OPiv)2 promoted C–H cycloamination of N-benzyl-2-aminopyridines to access pyrido[1,2-a]benzimidazoles

N

N

Me

8 h, 91%

N

N7 h, 92%

N

N5 h, 65%

HFIP, 25 °Cair, 5–24 h

PhI(OPiv)2 (2.2 equiv)N

N

N

N

7 h, 97%

I Ph

N

NH

R1

R2

(1 equiv)

R1

R2


N

NNC

N

N

F3C

24 h, 91%

N

N

11 h, 89% Me

Cl

N

N11 h, 89% 12 h, 91%


N NH

N NI

Ph OPiv

N N

+F3C

CF3

OH

– H+

N N ORN N ORIPh

PivO

ROH

N N

IPh

PivO– H+

N

N

H + – H+N

N

4445

464748

– PhI

– PivOH

PhI(OPiv)2

– OPiv

– CH2(OR)2

– PivOH– PhI R = (CF3)2CH

PhI(OPiv)2

– PivOH

49


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ing and highly regioselective directing group in its cross-annulation reaction with 2-aminoquinoline (Scheme 36).To obtain the requisite starting material 56, xylene was

treated with PhI(OAc)2 to form benzylic radical 54, whichwas subsequently converted into cation 55 by the PhI(OAc)free-radical species. Nucleophilic attack of 2-aminoquino-line onto cation 55 gave benzylic amine 56, which was con-verted into the final product via a mechanism akin to thatdescribed in Scheme 32.

In the same year, Das et al. reported a hypervalentiodine(III) [PhI(OH)OTs, Koser’s reagent] catalyzed, regio-selective C–H cycloamination reaction of various N-aryl-2-aminopyridines for the synthesis of pyrido[1,2-a]benzimidaz-oles in excellent yields (Scheme 37).32 Hypervalent iodine(III)was generated in situ by using iodosobenzene diacetate in acatalytic amount and p-toluenesulfonic acid monohydrateand m-chloroperbenzoic acid in stoichiometric amounts.Use of water as a solvent and open-flask chemistry makesthe protocol greener and more significant for large-scalesynthesis of diversified pyrido[1,2-a]benzimidazole deriva-tives.

The following plausible mechanism was proposed forthe PhI(OH)OTs-catalyzed oxidative C–N bond-formationreaction of N-phenyl-2-aminopyridine (Scheme 38). Thereaction starts with the interaction of in situ generatedPhI(OH)OTs with N-phenyl-2-aminopyridine, generatingthe electrophilic N-iodo species 57. The formation of inter-mediate 58 occurs next by electrophilic annulation on the

Scheme 33 Synthesis of pyrido[1,2-a]benzimidazoles via metal-free annulations of 2-aminopyridines with arenes

N

NH2

R1 + R2PhI(OAc)2 (2 equiv)

HFIP, 40 °C, 12 hN

NR1

R2

N

N

O

N

N

Me

N

N

Me

Me

N

N

iPr

iPr

N

N

OMe

NC

80% 67%

52%

68%

N

N

F

Me

Me

N

N

Me

Me

Me

59% 75%

N

N

Me

Me

Me

AcO

80%

(1 equiv) (5 equiv) 20 examples43–87% yield

75%


Scheme 34 Synthesis of quinolino[1,2-a]benzimidazoles via metal-free annulations of 2-aminoquinolines with arenes

N NH2

+

PhI(OAc)2

(3 equiv)

HFIP, 40 °C, 18 h

NN

R1

Me

R2

R1

R2

NN

Me

NN

I

NN

Me

Me

Me

NN

Me

NN

Me

NN

Me

F

Me Ph 60% 45% 39%

57% 47% 56%

(1 equiv)(5 equiv)


Scheme 35 Proposed mechanism for the PhI(OAc)2-mediated annula-tion of 2-aminopyridine with p-xylene

N

NH2 PhI(OAc)2

AcOH

N

NH

IOAcPh Me

Me

N

NMe

Me

N

HN

Me

Me

N

N

H

Me

MeAcO

N

N Me

Me

AcOH

IOAcPh

PhI(OAc)2

AcOH

PhI + AcO

PhI + AcO

50

51

52

53

Scheme 36 Proposed mechanism explaining the PhI(OAc)2-mediated annulation of 2-aminoquinoline with p-xylene

Me

Me

CH2

Me

CH2

Me

PhI(OAc)2

– AcOH

PhI(OAc)NH2N

– AcOH– PhI

N NH

Me54 5556

mechanism akin to Scheme 32

N

N

Me

Scheme 37 Koser’s reagent catalyzed, regioselective C–H cycloamina-tion of N-aryl-2-aminopyridines

N

N

t-Bu

4 h, 98%

N

N

O

O

6 h, 94%

N

N

Cl

F

6 h, 82%

PTSA·H2O (2 equiv) H2O, rt, 4–6 h

PhI(OAc)2 (20 mol%)

NH

NN

N

m-CPBA (1 equiv)

N

N4 h, 90%

R1

R1R2

(1 equiv)

R2


N

N

CF3

6 h, 88%

N

N

6 h, 95% OEt

N

N6 h, 92%

OCF3

N

N

6 h, 72%

OMe



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pyridine nitrogen of N-iodo species 57, followed by depro-tonation of 58 to give the final product. The eliminated PhIenters the catalytic cycle upon its oxidation by m-CPBA inthe presence of PTSA·H2O to generate the reactive io-dine(III) PhI(OH)OTs, thus completing the catalytic cycle.Further, the rationale behind the high regioselectivity ofthis method is the favored formation of intermediate 60over 59 due to steric effects (Scheme 39), to afford oneregioisomer exclusively.

The Patel group reported a one-pot, three-componentcyclocondensation reaction of (aryloxy)pyrazole-4-carbal-dehyde, malononitrile, and 2-(cyanomethyl)benzimidazolecatalyzed by piperidine to give newer (aryloxy)pyrazole-substituted pyrido[1,2-a]benzimidazole derivatives (Scheme40).33 This methodology allows an easy and expedient as-similation of two promising bioactive nuclei, namely (ary-loxy)pyrazole and pyrido[1,2-a]benzimidazole into a singlemolecule for antimicrobial screening.

In 2014, the Xu group described the use of hypervalentiodine(III) in the expedient preparation of imidazo[1,2-a]pyrimidine derivatives in good yields from readily avail-able N-aryl-2-aminopyrimidines (Scheme 41).34 This pro-cess involves the intramolecular C(sp2)–H bond cyclo-amination reaction of N-aryl-2-aminopyrimidines promot-ed by hypervalent iodine(III) formed in situ fromstoichiometric iodobenzene bis(trifluoroacetate) (PIFA).Various N-aryl-2-aminopyrimidines were employed to es-tablish the wide scope of this method.

The authors proposed two mechanistic pathways to ex-plain the hypervalent iodine(III)-catalyzed cycloaminationof N-phenyl-2-aminopyrimidine (Scheme 42). A nucleo-philic substitution reaction of the aniline nitrogen onto theiodine(III) center of PIFA forms intermediate 61. In path A,intermediate 61 is transformed into nitrenium ion 62through an oxidative process, followed by the nucleophilicaddition of the pyrimidyl nitrogen atom on the carbon cen-ter of the carbocationic form 63 of intermediate 62 to give acyclic intermediate 64. Upon deprotonative rearomatiza-

Scheme 38 Plausible mechanism for Koser’s reagent catalyzed, regio-selective C–H cycloamination of N-phenyl-2-aminopyridine

PhI(OAc)2 +

PTSA·H2O

PhI(OH)OTs

N

NH+

TsOHPhI

+H

NH

N

N

NN

NIOTs

Ph

+

57

58

Scheme 40 One-pot, three-component synthesis of various (aryloxy)pyrazole-substituted pyrido[1,2-a]benzimidazole compounds

NN

Me

O

CHO

R1

R2

+CN

CN

N

HN CNR3

NN

Me

OR1

R2

N

NC

NCNH2

N

R3

NN

Me

ON

NC

NCNH2

N

NN

Me

O

Me

N

CN

NC

NH2

N

NN

Me

OMeN

NC

NCNH2

N

NN

Me

OMe

MeO

N

NC

NCNH2

N

NN

Me

O

MeO

N

NC

NCNH2

N

Me

+

NN

Me

OMeN

NC

NCNH2

N

Me

NN

Me

OMe

MeO

N

NC

NC NH2

NMe

NN

Me

OMe

Cl

N

NC

NC NH2

N Me

(1 equiv)(1 equiv)

(1 equiv)

piperidine (0.2 equiv)

EtOH, reflux, 3.5 h


75% 67%

83%

68%

67%

82%

69% 60%


Scheme 39 Reaction path for the regioselective C–H cycloamination of meta-substituted N-phenyl-2-aminopyridine

N

NH

R2

N

N

IPh OTs

R2

favored

meta-substitution

N

N

IPh OTs

not favored

R2

N

N

R2

+

only 7-isomer

PhI(OH)OTs

– H2O

60

59


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tion of 64, the desired product is produced. Alternatively,the direct nucleophilic substitution of the pyrimidyl nitro-gen on the aniline ring of intermediate 61 affords the cyclicintermediate 64, along with the release of one moleculeeach of PhI and CF3COO–.

Scheme 42 Mechanism proposed for the intramolecular C(sp2)–H bond cycloamination of N-phenyl-2-aminopyrimidine catalyzed by PIFA

Foroumadi and his group synthesized a series of pyri-do[1,2-a]benzimidazole derivatives by the reaction be-tween 2-(1H-benzo[d]imidazol-2-yl)acetonitrile and ethyl2,4-dioxo-4-arylbutanoates, using piperidine as a base inrefluxing EtOH (Scheme 43).35 Various ethyl 2,4-dioxo-4-arylbutanoates were used to establish the substrate scopeof the method. Mild reaction conditions, short reactiontimes and easy purification of the obtained compounds arethe significant advantages of this reaction from a syntheticpoint of view.

Scheme 43 Piperidine-catalyzed synthesis of pyrido[1,2-a]benzimid-azole derivatives

The mechanism that explains this conversion (Scheme44) starts with the formation of intermediate 65 by a Kno-evenagel condensation reaction between 2-(1H-ben-zo[d]imidazol-2-yl)acetonitrile and ethyl 2,4-dioxo-4-phenylbutanoate. Intramolecular nucleophilic addition ofthe benzimidazole ring nitrogen on the carbonyl carbon oc-curs, followed by dehydration to give the desired pyri-do[1,2-a]benzimidazole derivative.

Scheme 44 Proposed mechanism for the synthesis of diversely sub-stituted pyrido[1,2-a]benzimidazoles

Subsequently, Deng and his group developed an expedi-ent, molecular iodine-mediated preparation of pyrido[1,2-a]benzimidazole derivatives, using 2-aminopyridines andnon-aromatic cyclohexanones as starting materials undermetal-free conditions (Scheme 45).36 Molecular oxygen wasemployed as a green oxidant for the dehydrogenation–aro-matization of non-aromatic cyclohexanones which wereused as an aryl source in this protocol. A library of pyri-do[1,2-a]benzimidazoles was prepared in good to excellentyields by using various 2-aminopyridines and cyclohex-anones to establish the general applicability of this method.

Scheme 41 PIFA-catalyzed intramolecular cycloamination of N-aryl-2-aminopyrimidines


X

N

NH

XR1 R2

X = CH, N

PIFA (1.5 equiv)

MeCN20 min, rt X

NR1

NX

R2

N

N

NN

N

N

Me

NN

NMe

88% 82% 75%

N

N

N

CO2Et

97%

N

N

N Cl

N

N

N

Br

78%

75%

N

N

N

Ph

90%

N

N 58%


N

N

HN

N

N

NI

Ph TFA

PIFA CF3CO2H

N

N

N XI

Ph TFA

N

N

N

H

N

N

N

N

N

NI

Ph TFA

N

N

N

H N

N

N

H

PhI + TFA

PhI + TFA

H

Path A

Path B

61

62

63

64

NH

N CN

ArOEt

O

OO

N

N

Ar

CN

CO2Et

piperidine(0.5 equiv)

EtOH, reflux25–45 min

+

(1 equiv) (1 equiv)10 examples65–95% yield

N

N

CN

CO2Et

F

N

N

CN

CO2EtN

N

CN

CO2Et

Cl

N

N

CN

CO2Et

Cl

Cl

N

N

CN

CO2Et

Me

N

N

CN

CO2Et

OMe

90% 80% 85%

95% 65% 87%

OMe


NH

N CN

PhOEt

O

OO

+

Knoevenagelcondensation N

H

N

CN

O

PhOEt

O

N

N

Ph

CN

OEt

O

OH

– H2ON

N

Ph

CN

OEt

O

65

piperidine


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Scheme 45 I2-catalyzed synthesis of pyrido[1,2-a]benzimidazole deriv-atives from 2-aminopyridines and non-aromatic cyclohexanones

Two plausible reaction pathways were proposed to ex-plain the metal-free synthesis of pyrido[1,2-a]benzimidaz-ole, as shown in Scheme 46. Iodination of cyclohexanoneforms 2-iodocyclohexanone (66), which, upon nucleophilicsubstitution by 2-aminopyridine, generates the second in-termediate 67. Subsequent intramolecular cyclization of 67followed by deprotonation and dehydration leads to 6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine intermediate68 (path A). Molecular oxygen assisted dehydrogenation of68 forms the final product. In an alternative pathway, theinitial step is the condensation of 2-aminopyridine withcyclohexanone to give imine intermediate 69, which is sub-sequently isomerized to intermediate 70 (path B). Iodina-tion of 70 forms intermediate 71, which is isomerized intoanother intermediate 72. Intramolecular substitution of theiodo group with amine in 72 also affords intermediate 68.

In 2016, Zhang et al. reported a phenyliodine(III) di-acetate (PIDA) mediated intramolecular C(sp2)−H bondcycloamination reaction of 4-anilinoquinazolines usingmild reaction conditions to afford erlotinib drug-relatedbenzimidazo[1,2-c]quinazoline derivatives in appreciableyields (Scheme 47).37 This metal-free C–N coupling protocolwas found tolerable to both electron-donating and elec-tron-withdrawing groups at various substitution positionsof the aniline fragment of the starting materials used.

A plausible mechanism (Scheme 48) involves initiationby the interaction of PhI(OAc)2 with 4-anilinoquinazoline togive intermediate 73 that contains the electrophilic N-iodomoiety, with the subsequent loss of a molecule of aceticacid. Electrophilic annulation on the pyridine nitrogenthrough the cleavage of the N–I bond leads to the formationof another intermediate 74 along with the concurrent re-lease of one molecule each of PhI and acetic acid. In the fi-nal step, the deprotonative rearomatization of intermediate74 occurs, leading to the formation of the desired product.

N NH2

O

+I2 (1 equiv) N

N

N

N

N

N

N

N

N

N

88% 80%

Br

Me

Me

78%

Ph

Cl2CHCHCl2160 °C, O2, 24 h

R1

R2


R1

R2


N

N

Cl

88%

N

N

Br

Me 82%

N

N

t-Pent

68% 88%

N

N

CO2Et

83%


Scheme 46 Plausible reaction pathways for the I2-mediated synthesis of pyrido[1,2-a]benzimidazole

+

– H2O

N

N

N

NH

N

NH

I NH

N

I

H+

– HI

I2

N NH2O

[O]

69

70

Path A

N NH2

O

N

N

I2

– HI

N

N

N NH2

OI

[O]

N

N

Path B

– I – H2O– H+

66

67

68

68

71 72

Scheme 47 Synthesis of benzimidazo[1,2-c]quinazolines via metal-free C–N coupling of 4-anilinoquinazolines

N N

NH

PhI(OAc)2 (2 equiv)

N

N

N

N

N

N

O

O

O

ON

N

NO

O

OO

Me 83% 86%

HFIP, 40 °C, 0.5 h, air

R1

R2

(1 equiv)

R1

R2


N

N

NO

O

O

O

F 81%

N

N

NO

O

OO

COMe 66%

N

N

NO

O

OO

OMe

MeO 50%

N

N

NO

O

OO

55%


Scheme 48 Plausible mechanism for the PhI(OAc)2-promoted cyclo-amination of 4-anilinoquinazoline

N N

NH

N N

N

N N

N

IOAc

PhAcO

– AcOH – AcOH– PhI

– H+

I PhAcO

73

74

N N

N


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During the same year, Yu and his group demonstratedthe use of molecular iodine as an oxidant for the intra-molecular C(sp2)−H bond cycloamination of N-arylpyridin-2-amines to construct a diverse range of pyrido[1,2-a]ben-zimidazoles, employing K2CO3 as a base under mild reactionconditions (Scheme 49).38 The optimized reaction condi-tions worked well with various substituted N-arylpyridin-2-amines.

Scheme 49 I2-mediated intramolecular aryl C–H amination of N-aryl-pyridin-2-amines to access pyrido[1,2-a]benzimidazoles

Depending upon the substitution on the aryl ring of theN-arylpyridin-2-amines, three plausible mechanisms(Schemes 50–52) were proposed for their direct I2-mediat-ed C–H cycloamination. The substrates with methyl substi-tution at the para position of the N-phenyl ring undergobase-mediated oxidative iodination to produce the electro-philic N-iodo species 75, followed by N–I bond cleavage andsubsequent intramolecular C–N bond formation to generateintermediate 76, which undergoes deprotonative rearoma-tization to form the corresponding final product (Scheme50). When N-phenylpyridin-2-amine is used as the startingmaterial, the initial step is the attack of a molecule of N-phenylpyridin-2-amine on the para position of its N-iodoform to give dimer 77; subsequent I2-mediated oxidativecycloamination affords the product (Scheme 51). 2,4,6-Trimethylphenyl-bearing substrates undergo intramolecu-lar nucleophilic substitution of the pyridine nitrogen ontothe aryl ring carbon to give intermediate 78. Iodide-ion-as-sisted demethylation of 78 yields the corresponding finalproduct (Scheme 52).

Verma and co-workers recently described an eco-be-nign tandem method of preparation of various benzimid-azo-fused heterocyclic compounds, namely benzimidazo-fused benzofuro[3,2-c]pyridines, benzimidazo-fused ben-zofuro/benzothieno[2,3-c]pyridines, and benzimidazo-fused benzoindolo[3,2-c]pyridines, by using functionallyvaried alkynyl aldehydes and o-phenylenediamines asstarting materials in aqueous medium under transition-

metal-free conditions (Scheme 53).39 The reaction occursthrough a one-pot inter- and intramolecular C–N bond for-mation via regioselective 6-endo-dig cyclization.

A plausible mechanism for the formation of benzimid-azo-fused polyheterocycles (Scheme 54) involves the initialreaction between the alkynyl aldehyde and o-phenylenedi-amine to furnish the corresponding imine intermediate 79.Subsequent intramolecular nucleophilic attack of the aminogroup on the imine bond generates the cyclic intermediate80, which upon auto-oxidation forms the benzimidazole-

N

NH

R1 R2

N

NR1

R2I2 (3 equiv)K2CO3 (4 equiv)

1,4-dioxane, 60 °C10 examples65–95% yield

N

NMe

N

NMe

Me

N

NMe

OMe

5 h, 70% 5 h, 92%

5.5 h, 91%

N

NN

MeN

6 h, 94%

N

N

Me

Me

Me

4.5 h, 95%

N

NMe

Me

Me

9 h, 95%

N

NMe

Me

Br

5 h, 65%

(1 equiv)


Scheme 50 I2-mediated intramolecular aryl C–H amination of p-methyl-substituted N-phenylpyridin-2-amine

N

MeN

HII Base

N

MeN

I

N

NH

Me

Base

N

N Me

75

76

Scheme 51 I2-mediated intramolecular aryl C–H amination of N-phenylpyridin-2-amine

N

N

HI IBase

N

N

I

NH Ph

N

N

NN

H

H

Ph

N

N

NN

Ph

N

I

N

NN

Ph

N

HI IBase

NPh

N

N

NH

NPh

N

N

N

77

Scheme 52 I2-mediated intramolecular aryl C–H amination of 2,4,6-trimethyl-substituted N-phenylpyridin-2-amine

N

N

HI IBase

N

N

I

Me

N

NMeMe

N

N

MeMe

Me

Me

Me

Me

Me

I

Me78


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fused intermediate 81. A second intramolecular nucleophil-ic attack by the benzimidazole ring nitrogen on the electro-philic alkyne bond produces the unstable vinylic anion 82,which is protonated to give the final product.

Scheme 54 Mechanistic explanation for the metal-free synthesis of benzimidazo-fused heterocyclic compounds

3 Conclusion

In summary, pyrido[1,2-a]benzimidazole and its ana-logues have taken a leading role in the recent literature, be-cause of their wide variety of applications in various disci-

plines such as medicinal chemistry and materials science.Several novel synthetic routes have been developed to pro-duce these scaffolds, involving mainly construction of theimidazole ring on the pyridine nucleus and scantly the op-posite. These newer synthetic routes are based on the com-bination of several interesting strategies such as multicom-ponent reactions, tandem sequences, and C–H activation.As is evident from the discussion in this review, these syn-thetic procedures offer easy access to pyrido[1,2-a]benzim-idazole from simple and readily available precursors with-out the need of any prefunctionality. The development ofthese synthetic procedures is very useful, especially for me-dicinal and materials chemists.

Acknowledgement

Sk.R. thanks CSIR-New Delhi for his research fellowship.

References

(1) (a) Hranjec, M.; Piantanida, I.; Kralj, M.; Suman, L.; Pavelic, K.;Karminski-Zamola, G. J. Med. Chem. 2008, 51, 4899. (b) Ndakala,A. J.; Gessner, R. K.; Gitari, P. W.; October, N.; White, K. L.;Hudson, A.; Fakorede, F.; Shackleford, D. M.; Kaiser, M.; Yeates,C.; Charman, S. A.; Chibale, K. J. J. Med. Chem. 2011, 54, 4581.

(2) (a) Morgan, G.; Stewart, J. J. Chem. Soc. 1938, 1292. (b) Morgan,G.; Stewart, J. J. Chem. Soc. 1939, 1057.

Scheme 53 Metal-free synthesis of various benzimidazo-fused heterocyclic compounds from alkynyl aldehydes and o-phenylenediamines

18 examples reported68–92% yield

O

O

H

R2

O

N

N

R2

R1

8–12 h(1 equiv)

X

H2O, 100 °C

6–10 h

(1 equiv)

R2

O

H

X = O, S 6 examples reported80–92% yield

N

N

R2

R1

XNH2

NH2

R1

(1 equiv)10–18 h

N

O

H

R2

(1 equiv)Me

12 examples reported73–88% yield

N

N

N

R2

R1

Me

H2O, 100 °CH2O, 100 °C

O

N

N

O

N

N

t-Bu 88% 92%

O

N

N

68%


O N

N

OMe 92%

S N

N

80%

N

N

N

OCF3 73% 86%

N

N

N

Me

N

N

N

88%Me

Me

MeMe

S

O

H

R2

NH2

NH2

X

Het

N

R2

X

HetH2O

H2N

R2

X

HetNH

HN

R2

X

HetNH

N

XHet

N

R2

N

XHet

N

R1

N

H+

79

80

81

82


2149


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