application of organic azides for the synthesis of nitrogen...

ACCOUNT 21

Application of Organic Azides for the Synthesis of Nitrogen-Containing MoleculesShunsuke Chiba*Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, SingaporeFax +6567911961; E-mail: [email protected] 31 May 2012

SYNLETT 2012, 23, 21–44xx.xx.2011Advanced online publication: 09.12.2011DOI: 10.1055/s-0031-1290108; Art ID: A59911ST© Georg Thieme Verlag Stuttgart · New York

Abstract: In this account, recent advances made on the reactions ofseveral types of organic azides, such as vinyl azides, cyclic 2-azidoalcohols, a-azido carbonyl compounds, towards the synthesis ofnitrogen-containing molecules are described.

1 Introduction2 Chemistry of Vinyl Azides2.1 Thermal [3+2]-Annulation of Vinyl Azides with 1,3-Dicar-

bonyl Compounds2.2 Manganese(III)-Catalyzed Formal [3+2]-Annulation with

1,3-Dicarbonyl Compounds2.3 Manganese(III)-Mediated/Catalyzed Formal [3+3]-Annu-

lation with Cyclopropanols2.4 Synthesis of Isoquinolines from a-Aryl-Substituted Vinyl

Azides and Internal Alkynes by Rhodium–Copper Bimetal-lic Cooperation

3 Chemistry of Cyclic 2-Azido Alcohols3.1 Manganese(III)-Catalyzed Ring Expansion of 2-Azido-

cyclobutanols3.2 Palladium(II)-Catalyzed Ring Expansion of Cyclic 2-Azido

Alcohols4 Chemistry of a-Azido Carbonyl Compounds4.1 Orthogonal Synthesis of Isoindole and Isoquinoline Deriv-

atives4.2 Generation of Iminylcopper Species and Their Catalytic

Carbon–Carbon Bond Cleavage under an Oxygen Atmo-sphere

4.3 Copper(II)-Catalyzed Aerobic Synthesis of Azaspirocyclo-hexadienones

5 Conclusion

Key words: azides, nitrogen-containing heterocycles, radical reac-tions, redox reactions, oxygenations

1 Introduction

The chemistry of organic azides commenced with the syn-thesis of phenyl azide by Griess in 18641 and the discov-ery of the rearrangement of acyl compounds withhydrogen azide (HN3) by Curtius in 1890.2 Since 1950,various synthetic organic reactions have been developedusing acyl, aryl, and alkyl azides, which have been exten-sively applied for the synthesis of nitrogen-containingazaheterocycles as well as peptides.3

Organic azides possess diverse chemical reactivities.4

Owing to their 1,3-dipole character, they undergo [3+2]cycloaddition with unsaturated bonds, such as those inalkynes and alkenes as well as carbonitriles (Scheme 1,part a).5 Organic azides can also be regarded as nitreneequivalents (Scheme 1, part b).6 Accordingly, their reac-tions with nucleophilic anions, electrophilic cations, andradicals can formally provide the corresponding nitrogenanions, cations, and radicals, respectively, forming a newbond with the internal azido nitrogen and releasing molec-ular nitrogen. Moreover, the generation of anions, cations,and radicals at the a-position to the azido moiety can re-sult in rapid denitrogenation to deliver the correspondingiminyl species, which can be used in further synthetictransformations (i.e., carbon–nitrogen bond formation).

Scheme 1

We have been interested in the intriguing chemical reac-tivity of organic azides, such as vinyl azides, cyclic 2-azi-do alcohols, and a-azido carbonyl compounds(Scheme 2). In this account, we describe recent advancesmade on the reactions of these organic azides towards thesynthesis of nitrogen-containing molecules which havebeen developed in our research group.

N N NR

(a) 1,3-Dipoles

(b) Nitrene equivalents

N N NR

C C

C C

C NC N

NN

NR

C CN

NNR

C CN

NNRalkenes

alkynes

nitriles

+triazolines

triazoles

tetrazoles

N N NR NRnitrenes

+ N2

N N NR + C+

with carbocations

N CR

N N NR + X–

with carbanions or other nucleophiles

N XR

N N NR + C

with carbon radicals

N CR

+ N2

+ N2

+ N2

N N NC

chemistry of α-azido anions, cations, and radicals

NC + N2

N N NC NC + N2

N N NC NC + N2

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22 S. Chiba ACCOUNT

Synlett 2012, 23, 21–44 © Thieme Stuttgart · New York

Scheme 2

2 Chemistry of Vinyl Azides

Intermolecular annulation reactions can allow for thestraightforward and selective construction of complex cy-clic molecular structures in a one-pot manner from rela-tively simple building blocks, one of the most idealprocesses in organic synthesis from an atom-7 and step-economical8 point of view. Inspired by this perspective,we have recently been interested in the application of vi-nyl azides as a three-atom unit including one nitrogen forvarious types of annulation reactions to prepare azahet-erocycles.

One of the attractive chemical properties of vinyl azides istheir ability to undergo thermal decomposition to givehighly strained three-membered cyclic imines, 2H-azir-ines, via vinylnitrene intermediates following denitroge-nation (Scheme 3, part a).9 Moreover, the carbon–carbondouble bond of vinyl azides can be used for the formationof new carbon–carbon bonds with appropriate organome-tallic compounds (R′–[M]) or radical species (R¢) whichresults in the generation of iminyl metals or iminyl radi-cals, respectively (Scheme 3, parts b and c).10 These im-

inyl species serve for the formation of carbon–nitrogenbonds. In this section, we present the synthesis of azahet-erocycles from vinyl azides via several types of reactionmode based on the above chemical reactivities.

2.1 Thermal [3+2]-Annulation of Vinyl Azides with 1,3-Dicarbonyl Compounds

During the course of our study on the chemistry of 2H-azirine derivatives,11 it was found that the reaction of azir-ine 1 with acetylacetone (2) in 1,2-dichloroethane at roomtemperature gave tetrasubstituted pyrrole 3 in quantitativeyield after 33 hours (Scheme 4).

Scheme 4

While the reaction of azirine 1 with acetylacetone (2) intetrahydrofuran (THF) has been reported, the yield of pyr-role 3 was low.12 The generation of 3 in high yield in theabove reaction (Scheme 4) led us to further investigate thepyrrole formation.

The reaction may proceed through the addition of acetyl-acetone (2) to the imino carbon of azirine 1,13 followed bynucleophilic attack of the nitrogen in the resulting aziri-dine to a carbonyl group with concurrent ring opening ofthe strained three-membered ring.14 However, the insta-bility and poor accessibility of the 2H-azirines preventedus using this strategy as a synthetic method for pyrroles.Accordingly, we planned to use vinyl azides as precursorsof 2H-azirines which can be easily synthesized15 and han-dled (Scheme 5).

As proposed in Scheme 5, simple heating of a mixture ofethyl 2-azido-3-(2,6-dichlorophenyl)acrylate (4) andacetylacetone (2) in toluene at 100 °C provided pyrrole 5in 86% yield (Table 1, entry 1).16 Various 2-azido-substi-tuted cinnamates possessing electron-donating and -with-drawing groups on the phenyl group (entries 2–8), as wellas a derivative containing a pyridyl moiety (entry 9), re-acted with acetylacetone (2) to give the corresponding 2-

R

NNN

vinyl azides

HO NNN

cyclic 2-azido alcohols

R

N

O

R'

NN

a-azido carbonyl compounds

Scheme 3

R

NNN

R

N N

R

– N2

vinylnitrenes 2H-azirines

R

NNN

R'–[M]

– N2

R'

R

NNN

R'[M]

R

NR'

[M]

R

NNN

– N2

R

NNN

R'R

NR'

(a)

(b)

(c)

Δ

Shunsuke Chiba was bornin Zushi, Kanagawa, Japan,in 1978. He obtained hisB.Eng. from Waseda Uni-versity in 2001 and receivedhis Ph.D. in 2006 from the

University of Tokyo (work-ing under Professor KoichiNarasaka). He was appoint-ed as a research associate atthe University of Tokyo in2005. In 2007, he moved to

Nanyang TechnologicalUniversity, Singapore, as anassistant professor. His re-search focus is methodologydevelopment in the area ofsynthetic organic chemistry.

Biographical Sketch

DCEr.t., 33 h

3 quant1

Cl

Cl

CO2EtN Me

O

Me

O

NH

EtO2C COMe

Me

Cl

Cl2 (1.2 equiv)

+

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ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 23

© Thieme Stuttgart · New York Synlett 2012, 23, 21–44

arylpyrroles in good yields. Vinyl azides 22 and 24 bear-ing acetyl and (dimethylamino)carbonyl moieties insteadof an a-ethoxycarbonyl group could be employed to givethe corresponding pyrroles 23 and 25 (entries 10 and 11,respectively). It is known that the thermolysis of 2-azido-substituted cinnamates and their derivatives delivers 1H-

indoles via intramolecular C–H amination.17,18 It is note-worthy that the above intermolecular reactions of 2-azido-substituted cinnamate derivatives with acetylacetone (2)gave pyrroles exclusively without any indole formation.

As b-substituents (R1) of azidoacrylates, ethoxycarbonyland alkyl groups could be introduced, giving the corre-sponding pyrroles in good yields (entries 12 and 13). Sim-ple azidoacrylate 30 also reacted smoothly (entry 14).Using a-aryl-substituted vinyl azides, not only phenylgroups, but also naphthyl, indolyl, pyrrolyl, and ben-zothiophenyl moieties could be installed at the 3-positionof the resulting trisubstituted pyrroles (entries 15–26). a-Alkyl-substituted vinyl azide 56 reacted smoothly to givethe corresponding pyrrole 57 in 82% yield (entry 27). AnE,Z-mixture of 2-phenylvinyl azide (58) could also beused to prepare trisubstituted pyrrole 59 in 85% yield (en-try 28). Tetrasubstituted pyrroles 61 and 63 were success-

Scheme 5

– H2O

A B

– N2– H2O

Me

O

Me

O+

2

R2

NR1

N2

R2R1

N

O

Me

O Me

HO

O

Me

Me

HNR2R1

HNH

COMe

MeOHR1

R2

NH

R1

R2 COMe

Me

– N2

Δ

Table 1 Synthesis of Pyrroles from Vinyl Azides and Acetylacetone (2)a

a Unless otherwise noted, the reactions were carried out by heating a mixture of the vinyl azide (0.3–0.5 mmol) and acetylacetone (2) (1.2 equiv) in toluene at 100 °C for 2–24 h.b Isolated yields are shown.c The reaction was performed at 85 °C for 16 h.d The reaction was performed at 85 °C for 20 h in the presence of acetylacetone (2) (2 equiv).e The reaction was performed at reflux for 5 h.

R1CO2Et

N3

CO2Et

N3R

NH

Me

COMeEtO2C

R

Entry Vinyl azides Pyrrolesb

5 86%7 93%9 90%11 89%13 96%15 90%17 90%19 81%

N

CO2Et

N3NH

Me

COMe

N

21 94%

EtO2C

NH

Me

COMe23 74%

R2

25 quant

20

R2

N3

NH

Me

COMe

R1

27 82%EtO2C

31 85%29 96%

9

N3 NH

Me

COMe

33 75%

NH

Me

OMeTsN 51 92%

NH

Me

OMeTsN

53 92%

NH

Me

OMe

Ph

57 82%

NH

Me

OMe

S

55 96%

NH

Me

COMe

59 85%

NH

Me

OMe

Me

63 91%

NH

Me

OMe

61 66%

N3

NTs

50

N3

NTs

52

N3

S 54

N3

Ph 56

58(E:Z = 1:1)

N3

60

N3

62

N3

24

25

26

27

28

29

30

N3

R

R 35 98%37 95%39 86%41 92%43 91%45 86%

NH

Me

COMe46 47 94%22

Entry Vinyl azides Pyrrolesb

4: R = 2,6-Cl26: R = H8: R = 4-Me10: R = 2-Me12: R = 3-NO214: R = 4-Br16: R = 4-CN18: R = 4-MeO

22: R2 = COMe24: R2 = CONMe2

26: R1 = CO2Et28: R1 = CH2Ph30: R1 = H

32: R = H34: R = 4-Me36: R = 4-OMe38: R = 2-OMe40: R = 4-Br42: R = 3-Br44: R = 4-CO2Me

NH

Me

COMe49 65%

N3

4823

12345678c

10d

11

1213e

14

15161718192021

Me

– N2– H2O

Me

O

Me

O+

2

R2

NR1

N2NH

R1

R2 COMe

Me

Δ

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24 S. Chiba ACCOUNT


fully synthesized from a,b-disubstituted vinyl azides 60and 62 (entries 29 and 30, respectively).

The scope of the reaction using different 1,3-dicarbonylcompounds was next investigated with several vinylazides (Table 2).16 The reactions of 1,3-diketones bearingterminal alkene moieties or phenyl groups, such as 64 or68, respectively, with several vinyl azides resulted in theformation of the corresponding pyrroles (entries 1–4). Thereactions of b-keto aldehyde 70 proceeded smoothly withvinyl azides 6 and 26 forming tri- and tetrasubstituted pyr-roles 70/71 and 73/74 in almost 1:1 ratios (entries 5 and 6,respectively), probably via nucleophilic attack of the ni-trogen atom to both carbonyl groups (see Scheme 5, A toB). However, the treatment of vinyl azides 6 and 58 witha b-keto ester, ethyl acetoacetate (75), resulted in sluggishreactions, giving the desired pyrroles 76 and 77 in only 30and 58% yield (entries 7 and 8, respectively) along withcomplex mixtures.

2.2 Manganese(III)-Catalyzed Formal [3+2]-Annulation with 1,3-Dicarbonyl Compounds

Besides the above-mentioned thermal [3+2]-annulation ofvinyl azides and 1,3-dicarbonyl compounds, we plannedto use the carbon–carbon double bond of vinyl azides forthe formation of a new carbon–carbon bond to initiate an-other type of annulation reaction.

Our reaction design was based on the addition of a carbonradical bearing a carbonyl group to the carbon–carbondouble bond of a vinyl azide to provide a new carbon–car-bon bond with the generation of an iminyl radical. The im-inyl radical would then intramolecularly form a carbon–nitrogen bond with the carbonyl, resulting in cyclizationleading to various azaheterocycles (Scheme 6).19,20 Theproposed process could potentially be achieved in a redoxcatalytic manner featuring two key redox steps: (1) oxida-tive generation of the radical species by the reaction ofradical sources with a metal oxidant [Mn] (to become[Mn–1]) (oxidative initiation) and (2) reduction of the re-sulting iminyl radical by [Mn–1] and its cyclization withthe intramolecular carbonyl group to give azaheterocyclesand regenerate [Mn] (reductive termination).

Scheme 6

Based on this concept, manganese(III) acetate, which hasbeen extensively used for oxidative radical reactions us-ing carbonyl compounds,21 was employed in the reactionof 1-phenylvinyl azide (32) and ethyl acetoacetate (75) inmethanol (MeOH) under a nitrogen atmosphere. As ex-pected, the reaction proceeded smoothly at 40 °C using 10mol% of manganese(III) acetate in the presence of aceticacid (AcOH), affording trisubstituted pyrrole 77 in 94%yield (Scheme 7). This catalytic reaction is initiated by the

oxidative initiation

R

NC

COH

radical sources

reductive termination

azaheterocycles

[Mn]

[Mn-1]

N2

H+

[Mn-1]

N

R

NN

C

CO

R

NC

CO

R

NC

CO[Mn]

R

NC

CO[Mn]

Table 2 Scope of the Reaction Using Different 1,3-Dicarbonyl Compoundsa

a The reactions were carried out by heating a mixture of the vinyl azide (0.3–0.5 mmol) and 1,3-dicarbonyl compound (1.2 equiv) in toluene at 100 °C for 2–24 h.b Isolated yields are shown.

NH

OEtO2C

Me65 90%

NH

OEtO2C

EtO2C

O O

NH

O

O

H

O

72 43%

71 54%

74 39%

73 41%

NH

CHOEtO2C

EtO2C

NH

EtO2C

EtO2C

O

NH

CHOEtO2C

NH

EtO2CO

Entry

1

Vinyl azides 1,3-Dicarbonyl compounds Pyrrolesb

8 64

64

32

68

70

32

2

3 64

NH

O

66 94%

67 80%

69 95%

6

4

5

6 70

CO2Et

N3Me

O O

EtO2CCO2Et

N326

N3

CO2Et

N3

EtO2CCO2Et

N3

26

6

CO2Et

N37

Me

O

OEt

O

75NH

Me

OOEtEtO2C

76 30%

58

75N3

77 58%

NH

Me

OOEt

8

+

+

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addition of manganese(III) enolate I to vinyl azide 32 inthe radical pathway, giving iminyl radical II with the re-lease of a manganese(II) [Mn(II)] species and molecularnitrogen. The reaction of iminyl radical II with the Mn(II)species affords iminylmanganese(III) [(alkylideneam-ino)manganese(III)] III, the nucleophilic attack of whichto a carbonyl group yields cycloaddition intermediate IV.Finally, protonation of IV with AcOH followed by dehy-dration yields pyrrole 77 along with regeneration ofMn(III).

The scope of this catalytic pyrrole formation was found tobe quite broad. A series of vinyl azides could be employedwith ethyl acetoacetate (75), as shown in Table 3.19b a-Aryl-substituted vinyl azides reacted smoothly to affordthe corresponding pyrroles in good yields (entries 1–9).Tetrasubstituted pyrrole 87 could be synthesized from 2-methyl-1-phenylvinyl azide (62) in good yield (entry 9).The reaction of 2-pyrrolylvinyl azide 52 gave bipyrrole 88in 68% yield (entry 10). 1,4-Dipyrroylbenzene 90 couldbe obtained by treatment of 1,4-bis(1-azidovinyl)benzene

Table 3 Manganese Acetate Catalyzed Reaction of Vinyl Azides with Ethyl Acetoacetate (75)a

a Reactions were performed in MeOH at 40 °C with 1.5 equiv of ethyl acetoacetate (75) under a N2 atmosphere.b Isolated yields are shown.c Vinyl azide 52 was recovered in 25% yield.d Vinyl azide 60 was recovered in 10% yield.e Vinyl azide 6 was recovered in 15% yield.

Entry Vinyl azides [MnIII]/mol% Time/h Product (yield/%)b

32: R = H78: R = 2-Br40: R = 4-Br44: R = 4-CO2Me82: R = 3-NO2

34: R = 4-Me38: R = 2-OMe 94: R = Ac

96: R = Si(t-Bu)Ph2

1234567

10101010101010

NH

CO2Et

MeR

2222244

77 (94)79 (94)80 (86)81 (88)83 (95)84 (78)85 (75)

8 20 2NH

CO2Et

Me

86 (83)

9

46

62NH

CO2Et

Me

Me

87 (72)

10

52

20 24NTs

NH Me

CO2Et

88 (68)c

14

15

20 1

NH

CO2Et

MeRO

97 (85)20 2

95 (94)

17 40 5 NH

CO2Et

MeO

Si O

OAc

t-Bu t-Bu100 (74)

18

99

30

5 2NH

CO2Et

MeEtO2C

101 (98)

19 20 24

NH

CO2Et

MeEtO2C

102 (78)e

20 2

N3

N3

11

89

40 24NH

HN

Me

Me

CO2Et

EtO2C

90 (48)

NH

CO2Et

Me16

60

40 1

98 (60)d

N3

R

N3

N3

Me

N3

NTs

N3

RO

N3

N3

OSi

OOAc

t-Bu

t-Bu

N3

EtO2C

N3

EtO2C

13 20 2NH

CO2Et

MeO

93 (85)92 N3

O

12

56

NH

CO2Et

Me

91 (90)

20 3

N3

6

Entry Vinyl azides [MnIII]/mol% Time/h Products (yield/%)b

N

R1

R2Me

O

OEt

O cat. Mn(OAc)3⋅2H2O

MeOH, 40 °C+

75NH

CO2Et

Me

R2

R1

N2

Scheme 7

Me

O

OEt

O+

Mn(OAc)3⋅2H2O (10 mol%)AcOH (2 equiv)

MeOH, 40 °C, 2 h

32

NH

CO2Et

Me

77 94%(1.5 equiv)

75

NN2

Me OEt

O O

75

O

EtOO

NPh

II

N

CO2Et

PhMe

OH

77

O

EtO O

NPh

[MnIII]

[MnII]

[MnII], N2

AcOH

AcOH

MnIII(OAc)3

N

Ph

NN

O[MnIII]

OMe

EtO

I

32

III

N

CO2Et

PhMe

O

IVH2O

[MnIII]

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26 S. Chiba ACCOUNT


(89) with 40 mol% of manganese(III) acetate, althoughthe yield was moderate (entry 11). a-Alkyl-substituted vi-nyl azides could also be used for this pyrrole formation,giving the corresponding pyrroles in good yields (entries12–17). Bicyclic pyrrole 98 was obtained in 60% yieldfrom 1-azidocyclooctene (60) (entry 16). Vinyl azide 99bearing a chiral polyol functionality22 could be convertedinto pyrrole 100 in 74% yield (entry 17). Azidoacrylatescould also be employed in the above catalytic process (en-tries 18 and 19). While the reaction of ethyl 2-azidoacry-late (30) needed only 5 mol% of manganese(III) acetate tocomplete within 2 hours, affording pyrrole 101 almostquantitatively (entry 18), that of 2-phenylvinyl azide 6 re-quired a longer reaction time (24 h), probably owing tosteric hindrance (entry 19).

Next, the generality of this reaction using different b-ketoesters was examined with 1-phenylvinyl azide (32) andethyl 2-azidoacrylate (30), as shown in Table 4.19b Byvarying the substituent on the b-keto ester through the useof 103–105, phenyl, ethoxymethyl, and cyclopropylgroups could be successfully installed at the C-2 positionof the resulting pyrrole to give products 106–111.

The reaction of acetylacetone (2) instead of b-keto esterswith vinyl azide 32 in the presence of 20 mol% of manga-nese(III) acetate was sluggish, and pyrrole 114 was ob-tained in low yield (21%) along with the recovery of vinylazide 32 (63%), even after 24 hours. To improve the prod-uct yield in the reaction with acetylacetone (2), otherMn(III) complexes were screened. Although manga-nese(III) acetylacetonate [Mn(acac)3] displayed no cata-lytic activity in this reaction, the use of 20 mol% ofmanganese(III) tris(pyridine-2-carboxylate) [Mn(pic)3]

23

afforded pyrrole 114 in 76% yield after 20 hours(Table 5).19b Treatment of other vinyl azides with acetyl-acetone (2) using 20 mol% of Mn(pic)3 led to the forma-tion of pyrroles 115–118 in moderate to good yields,whereas electron-deficient vinyl azide 30 delivered thedesired pyrrole 119 in only 28% yield along with a com-plex mixture. The reaction of 1,3-diphenylpropane-1,3-dione (112) with vinyl azide 32 gave a moderate yield ofpyrrole 120, probably owing to the steric hindrance of thebenzoyl group. The reaction of unsymmetrical 1,3-dike-tone benzoylacetone (113) with vinyl azides proceeded toafford pyrroles 121–123 in moderate to good yields as thesole products via carbon–nitrogen bond formation withthe less-hindered acetyl group.

b-Keto acids have been used as either a-carbonyl anion24

or radical25 equivalents with the elimination of carbon di-oxide. Our findings on the reactivity of vinyl azides to-wards the a-carbonyl radicals derived from b-keto estersand 1,3-diketones with Mn(III) catalysts drove us to ex-amine the reaction of vinyl azides and b-keto acids. In thiscase, Mn(acac)3 suitably catalyzed the reaction to synthe-size the corresponding substituted pyrroles.

The reactions of various vinyl azides with b-keto acid 124are summarized in Table 6.19a The reaction of a-aryl-sub-stituted vinyl azides with 124 provided the desired bicy-clic pyrroles in good yields (entries 1–6). Notably, thereaction of vinyl azide 50 bearing an a-indol-2-yl substit-uent resulted in the formation of 2,2¢-biindole derivative130 (entry 6). 2-Azidoacrylate derivatives 30 and 26

Table 4 Manganese Acetate Catalyzed Synthesis of Pyrroles from Vinyl Azides and 1,3-Dicarbonyl Compoundsa,b

a Reactions were performed in MeOH at 40 °C with 1.5 equiv of the 1,3-dicarbonyl compound under a N2 atmosphere.b Isolated yields are shown next to the corresponding products.

NH

CO2Et

106: 63% (32+103)

107: 72% (30+103)

NH

CO2Et

108: 55% (32+104)

109: 77% (30+104)

NH

CO2Et

EtO2C

OEt

NH

EtO2C

CO2Et

OEt

NH

CO2Et

110: 56% (32+105)

NH

EtO2C

CO2Et

111: 72% (30+105)

N

N

EtO2Cor

NH

CO2Et

R

NH

CO2Et

REtO2C

cat. Mn(OAc)3•2H2OAcOH (2 equiv)

MeOH, 40 °Cor+

R

O

OEt

O

(1.5 equiv)

32

30

O

OEt

O

EtOOEt

OO

OEt

OO

β-keto esters:

103 104 105

N2

N2

Table 5 Reactions of Vinyl Azides with 1,3-Diketones Catalyzed by Manganese(III) Tris(pyridine-2-carboxylate)a,b

a Reactions were performed with 0.3 mmol of the vinyl azide under a N2 atmosphere.b Isolated yields are shown next to the corresponding products.c Vinyl azide 32 was recovered in 27% yield.

NH

COMe

MeR

114: R = H; 76% (32+2)115: R = 3-NO2; 80% (82+2)116: R = 4-Me; 52% (34+2)

NH

COMe

Me

Me

117: 41% (62+2)

NH

COMe

Me

AcO

118: 71% (94+2)

NH

Me

O

121: R = H; 61% (32+113)122: R = 4-Br; 55% (40+113)123: R = 4-CO2Me; 85% (44+113)

NH

EtO2C

COMe

Me

119: 28% (30+2)

1,3-diketones:

Me

O

Me

OMe

OO

2 113

R3

O

R4

O+

(20 mol%)

AcOH (2 equiv)

MeOH, 40 °C NH

R1

R2

R4

(1.5 equiv)

O

R3

R1

N

R2

R

O O

112

NH

O

120: 32% (32+112)c

N

O OMn

3

N2

Dow

nloa

ded

by: U

nive

rsity

of O

xfor

d. C

opyr

ight

ed m

ater

ial.



could also be used, giving the corresponding bicyclic pyr-roles 131 and 132 in good yields (entries 7 and 8, respec-tively). In the case of vinyl azide 26, the presence of anethoxycarbonyl group at the b-position did not retard theprocess, which gave tetrasubstituted pyrrole 132 in 74%yield (entry 8).

The scope of the b-keto acids in the reaction was next in-vestigated with vinyl azide 32 (Table 7).19a Tetrahydro-pyrano[4,3-b]pyrrole 134 and 4,5-dihydro-1H-benzo[g]indole 136 were constructed in good yields byemploying b-keto acids 133 and 135 (entries 1 and 2, re-spectively). Bicyclic pyrroles 138 and 140 bearing largercarbocycles could also be synthesized in good yields (en-tries 3 and 4, respectively). In addition, linear b-keto acids141 and 143 could be employed, affording the trisubstitut-ed pyrroles 142 and 144 in good yields (entries 5 and 6,respectively). However, b-keto acid 145, the precursor ofa primary a-carbonyl radical, was not a viable substrate,giving only low yields of the desired pyrrole 146 evenwhen using stoichiometric amounts of different Mn(III)complexes (entry 7).

2.3 Manganese(III)-Mediated/Catalyzed Formal [3+3]-Annulation with Cyclopropanols

We next focused on the use of cyclopropanols as precur-sors of b-carbonyl radicals and investigated their additionreactions with vinyl azides followed by carbon–nitrogenbond formation (formal [3+3]-annulation).26

The reaction of 1-phenylvinyl azide (32) and 1-phenylcy-clopropanol (147) to give the target compound 2,6-diphe-

nylpyridine (148) was investigated. The possible reactionpathway is depicted in Scheme 8. The reaction is initiatedby the addition of b-carbonyl radical I, generated via theone-electron oxidation of cyclopropanol 147 using themetal oxidant [Mn], to vinyl azide 32, affording iminylradical II with the elimination of molecular nitrogen. Thereaction of iminyl radical II with [Mn–1] affords iminyl-metal species III, and its intramolecular nucleophilic at-tack to the carbonyl group gives cyclized intermediate IV.Subsequent protonation affords tetrahydropyridine V

Table 6 Scope of the Reaction with a b-Keto Acid Using Different Vinyl Azidesa

a Reactions were performed in DMF at r.t. with 1.5–3.0 equiv of b-keto acid 124 under a N2 atmosphere.b Isolated yields are shown.c 10 mol% of Mn(acac)3 was used.d 20 mol% of Mn(acac)3 was used.

Entry Vinyl azides Yield/%b

1

Pyrroles

2345

+

OO

OH

124(1.5–3 equiv)

NH

R1

cat. Mn(acac)3

DMF, r.t.

R1

N

R2 R2

N3

R32: R = H40: R = 4-Br44: R = 4-CO2Me38: R = 2-MeO36: R = 4-MeO

NH

R

125: 83c

126: 92d

127: 68d

128: 91d

129: 87d

N3

NTs

6NH

NTs

50 130: 78c

EtO2C

N3NH

EtO2C30 131: 68c

7

EtO2C

N3

CO2Et8 26

NH

EtO2C

EtO2C132: 74c

N2

Table 7 Scope of the Reaction Using Different b-Keto Acidsa

a Reactions were performed in DMF at r.t. with 1.5–3.0 equiv of the b-keto acid under a N2 atmosphere.b Isolated yields are shown.c 30 mol% of Mn(acac)3 was used.d 40 mol% of Mn(acac)3 was used and b-keto acid 135 was added via a syringe pump over 1 h.e 20 mol% of Mn(acac)3 was used.f Mn(pic)3 (1 equiv) was used; the use of Mn(acac)3 (1 equiv) afforded pyrrole 146 in only 10% yield.

Entry β-Keto acids Yield/%bPyrroles

1 134: 70c

2 135 136: 65d

137: n = 13

+

OO

OH

(1.5–3 equiv)NH

cat. Mn(acac)3

DMF, r.t.

32

N

R1

R2 R1

R2

O

OO

OHNH

O

OO

OHNH

O O

OH

n4 139: n = 2 NH

n 138: 81e

140: 82e

141: R = Et56 143: R = Ph

142: 84e

144: 82eNH

R

Me

R

OO

OHMe

O

OH

O7NH

146: 23f

133

145

N2

Scheme 8

HO Ph

Ph

NNN

[Mn]

NPhPh

O

NPh

OPh [Mn]

NPh

OHPh

NPh Ph

Ph

O

– H2O

[Mn-1], H+

N2

147

I

II

IV

V

32

148

H+

NPh Ph

PhO

VI

[O]

NPhPh

O

[Mn]

[Mn-1]

III

Dow

nloa

ded

by: U

nive

rsity

of O

xfor

d. C

opyr

ight

ed m

ater

ial.

28 S. Chiba ACCOUNT


along with regeneration of [Mn]. Dehydration of V andsubsequent oxidation result in the desired pyridine 148.

We commenced our study on the pyridine formation usinga stoichiometric amount of a Mn(III) complex for the ox-idation of cyclopropanol 14727 as well as dihydropyridineVI (Scheme 8). It was found that the treatment of a mix-ture of vinyl azide 32 and cyclopropanol 147 (1.5 equiv)with 1.7 equivalents of Mn(acac)3 in MeOH led to the rap-id consumption of vinyl azide 32 within 5 minutes at roomtemperature. Stirring for a further 1 hour after the additionof AcOH (2 equiv) afforded 2,6-diphenylpyridine (148) in84% yield (Scheme 9, part a). It was noted that other met-al oxidants, such as silver(I),28 iron(III),29 or copper(II)30

complexes, were not viable for this transformation.

Next, we intended to use a catalytic amount of Mn(acac)3

with another stoichiometric oxidant for the aromatizationof dihydropyridine VI to give 148 (Scheme 8). It was re-vealed that the treatment of a mixture of vinyl azide 32and cyclopropanol 147 with a catalytic amount ofMn(acac)3 (10 mol%) in MeOH also led to the consump-tion of vinyl azide 32 within 5 minutes at room tempera-ture. The subsequent addition of oxygen (under O2, 1 atm)and hydrogen chloride (HCl) (2 equiv) provided the de-sired pyridine 148 in 80% yield (Scheme 9, part b).

Scheme 9 Optimized reaction conditions for pyridine formationusing a vinyl azide and a cyclopropanol

Using Mn(acac)3 in both a stoichiometric and aerobic cat-alytic manner, the generality of this Mn(III)-mediated/cat-alyzed pyridine formation was investigated with variousvinyl azides (Table 8).26

By applying the stoichiometric use of Mn(acac)3 (condi-tions A), the reactions of a range of a-aryl-substituted vi-nyl azides with cyclopropanol 147 afforded 2,6-diarylpyridines in moderate to good yields. Heteroarylmotifs, such as pyrrolyl and indolyl groups, were success-fully incorporated into the product, as shown in the forma-tion of 156 and 157. The reaction of electron-deficientazidoacrylate 30 provided pyridine 158 in 51% yield.When the reactions of a,b-disubstituted vinyl azides 6, 62,and 60 were performed using Mn(acac)3 in MeOH, thegenerated b-carbonyl radical underwent self-coupling orhydrogen abstraction preferentially, leading to the desiredpyridines in only trace amounts. This indicated that theaddition of the b-carbonyl radical to the a,b-disubstitutedvinyl azides was extremely slow owing to the steric hin-drance of the b-substituents on the latter compounds. In-

terestingly, the corresponding reactions with Mn(pic)3 inacetonitrile provided 2,3,6-trisubstituted pyridines 159–161 in moderate yields. This was probably due to the lowsolubility of Mn(pic)3 in acetonitrile that would allowonly a low concentration of the generated b-carbonyl rad-ical so as to prevent its side reactions.

Next, the catalytic pyridine formation (using conditionsB) was examined for the synthesis of pyridines 148, 150,155, and 157. The yields of the corresponding pyridinesare shown in parenthesis in Table 8 and are almost compa-rable with those obtained under the stoichiometric condi-tions.

The scope of the cyclopropanols in the reaction was theninvestigated with 1-phenylvinyl azide (32) under both thestoichiometric and catalytic reaction conditions (condi-tions A and B, respectively), as shown in Table 9.26 1-Arylcyclopropanols were converted into the correspond-ing 2,6-diarylpyridines in good yields (entries 1–3).Moreover, some alkyl groups (entries 4–7) includingstrained cycloalkyls, as in substrates 170 and 172, and apiperidine moiety, as in compound 174, could be installed

+ N

32

147(1.5 equiv)

148 84%N

Mn(acac)3(1.7 equiv)

MeOH, r.t., 5 minunder N2

AcOH(2 equiv)HO

N2

Mn(acac)3(10 mol%)

MeOH, r.t., 5 minunder N2

HCl(2 equiv)

under O2

+ 147(1.5 equiv)

148 80%

(a)

(b)

32

Table 8 Manganese(III)-Mediated Pyridine Formation from Vinyl Azides and Cyclopropanol 147a,b

a Unless otherwise noted, the reactions were carried out under either conditions A or B; A: treatment of a mixture of the vinyl azide (0.3 mmol) and cyclopropanol 147 (1.5 equiv) with Mn(acac)3 (1.7 equiv) in MeOH at r.t. under a N2 atmosphere for 5 min, followed by the ad-dition of AcOH (2 equiv); B: treatment of a mixture of the vinyl azide (0.3 mmol) and cyclopropanol 147 (1.5 equiv) with Mn(acac)3 (0.1 equiv) in MeOH at r.t. under a N2 atmosphere for 5 min, followed by the addition of HCl in MeOH (3 M, 2 equiv) with an O2 balloon (1 atm).b Isolated yields are shown next to the corresponding products. The yields obtained under conditions B are shown in parenthesis.c Vinyl azide 78 was recovered in 30% yield.d A solution of cyclopropanol 147 and AcOH in MeOH was added to the vinyl azide and Mn(acac)3 via a syringe pump over 1 h.e The reactions were run using Mn(pic)3 (1.7 equiv) and AcOH (2 equiv) in MeCN at 40 °C at r.t.

+NR1

147(1.5 equiv)

R1

N

HO

conditions A: Mn(acac)3 (1.7 equiv), r.t., 5 min then AcOH (2.0 equiv), r.t. / MeOH

conditions B: Mn(acac)3 (10 mol%), r.t., 5 min then HCl (2.0 equiv) under O2, 40 °C / MeOH


NR

84% (80%)84%71% (70%)

47%c

70%70%

N

155 75% (72%)

70%

NN

Ts

156 70%d

NN

Ts

157 66% (50%)d

N

Me

N

160 45%e 161 52%e

158: R2 = H

NEtO2C

R2

51%30%e159: R2 = Ph

N2

R2

R2

Dow

nloa

ded

by: U

nive

rsity

of O

xfor

d. C

opyr

ight

ed m

ater

ial.



at C-2 of the pyridine ring. The introduction of alkenyland alkynyl groups on the pyridine ring was a particularfeature of this method (entries 8 and 9, respectively). Themethod also allowed for the installation of an alkoxycar-bonyl group as well as a dimethyl(phenyl)silyl moiety(entries 10 and 11, respectively). The reactions of vinylazide 32 and 1,2-disubstituted cyclopropanols 184 and186 with Mn(pic)3 afforded 2,4,6-trisubstituted pyridines185 and 187 (entries 12 and 13, respectively). In thesecases, secondary b-carbonyl radicals were found to beformed predominantly via the oxidative ring opening of184 and 186, judging from the substitution patterns of theproducts.

The catalytic reaction (conditions B) provided almostcomparable results for most of the substrates, except in thereactions to give pyridines 175 (entry 7) and 179 (entry 9).

We planned to broaden the reaction scope of this Mn(III)-mediated pyridine synthesis using other types of cyclo-propanols. The one-electron oxidation of 1-alkoxycyclo-propanols should generate b-alkoxycarbonyl radicals,which we also expected to add to vinyl azides. The reac-tion of vinyl azide 32 and 1-(ethyloxy)cyclopropanol(188) proceeded smoothly and rapidly (within 5 min) us-ing 10 mol% of Mn(acac)3 in ethanol (EtOH) at room tem-perature to result in the formation of d-keto ester 189 invery high yield (Scheme 10). In this case, the generatediminyl radical A was reduced by the resulting Mn(II) spe-cies to afford iminylmanganese(III) B, which could notundergo intramolecular cyclization with the ethoxycarbo-nyl group, but was protonated to give imine C with regen-eration of the Mn(III) species. Hydrolysis of imine Cduring the workup process delivered d-keto ester 189.

Scheme 10

To keep the nitrogen atom of the putative imine C in thefinal product, we tried to reduce imine C to give an amine,which would then undergo lactamization to provide a d-lactam.31,32 After the consumption of vinyl azide 32 in thereaction with cyclopropanol 188, sodium borohydride (2

equiv) was added to the reaction mixture, which providedd-lactam 190 in 85% yield as expected (Scheme 11). A se-ries of a-aryl-substituted vinyl azides possessing bothelectron-withdrawing and electron-donating groups were

• A proposed reaction mechanism

+

32

N

Mn(acac)3 (10 mol%)

EtOH, r.t., 5 minunder N2

HO OEt

Ph

NNN

OEt

O

OEtO

32

OEtHO Mn(III)

– Mn(II), H+

188(1.2 equiv)

OEt

O O

189 96%

OEt

N O

188

Mn(II)

OEt

N O

[Mn(III)]

H+

– Mn(III)

OEt

NH O

H2O

(workup)189

A

BC

N2

Table 9 Manganese(III)-Mediated Pyridine Formation from Vinyl Azide 32 and Cyclopropanolsa

a Unless otherwise noted, the reactions were carried out under either conditions A or B; A: treatment of a mixture of vinyl azide 32 (0.3 mmol) and the cyclopropanol (1.5 equiv) with Mn(acac)3 (1.7 equiv) in MeOH at r.t. under a N2 atmosphere for 5 min, followed by the ad-dition of AcOH (2 equiv); B: treatment of a mixture of vinyl azide 32 (0.3 mmol) and the cyclopropanol (1.5 equiv) with Mn(acac)3 (0.1 equiv) in MeOH at r.t. under a N2 atmosphere for 5 min, followed by the addition of HCl in MeOH (3 M, 2 equiv) with an O2 balloon (1 atm).b Isolated yields.c The reaction was run using Mn(pic)3 (1.7 equiv) in MeCN at r.t.

+

32 (1.5 equiv)

HO R1

EntryYield/%b

conditions A: Mn(acac)3 (1.7 equiv), r.t., 5 min then AcOH (2.0 equiv), r.t. / MeOH

conditions B: Mn(acac)3 (10 mol%), r.t., 5 min then HCl (2.0 equiv) under O2, 40 °C / MeOH

Cyclopropanols PyridinesCondition A Condition B

162: R = 2-Br164: R = 4-Br166: R = 4-Ph

1

N

7081

163165167 66

168

80 70

23

174

7

176

175

82 45

8 54

177

33

55

45

9

1011c

NN R2

HOR

82

R

HO

HO4

169

N

5170 73N

171

70

6HO

172173

N 78 70

HO NBn N

BnN

HO R3

HO N 51

HO178

N R3

179

N21

180: R3 = CO2Me182: R3 = SiMe2Ph

181183

184: R4 = Me186: R4 = Ph

HO

R4N

R4

185187

6340

12c

13c

R2

R1

N2

Dow

nloa

ded

by: U

nive

rsity

of O

xfor

d. C

opyr

ight

ed m

ater

ial.

30 S. Chiba ACCOUNT


transformed into aryl-substituted d-lactams 191–194 ingood yields.26a

Next, we envisaged using bicyclic cyclopropanols, suchas bicyclo[3.1.0]hexan-1-ol (195), as sources of b-carbo-nyl radicals. Interestingly, the unusual product 2-azabicy-clo[3.3.1]non-2-en-1-ol 196 was isolated in 89% yield onthe reaction of compound 195 with vinyl azide 32 usingonly a catalytic amount of Mn(acac)3 (5 mol%); the slowaddition of 195 via a syringe pump to a mixture of vinylazide 32 and the catalyst over 1 hour was required to com-plete the reaction (Scheme 12).26 It is noteworthy that thetreatment of optically active cyclopropanol 195 (85%ee)33 with vinyl azide 32 afforded racemic compound 196.The lack of transmission of the chirality of cyclopropanol195 to bicyclic product 196 suggests that the generation ofachiral ring-expanded b-carbonyl radical I34 from 195 fol-lowed by its radical addition to vinyl azide 32 is involvedin the reaction mechanism. The radical addition wouldform iminylmanganese(III) II-eq and II-ax bearing an im-inyl tether in an equatorial- and axial-like position, re-spectively. The conformational inversion of II-eq to II-axwould be indispensable for achieving the further intramo-lecular cyclization of iminylmanganese II-ax with thecarbonyl group to give alkoxymanganese(III) species III,which would protonate to afford 196.

Scheme 12

With the Mn(III)-catalyzed method to construct a 2-aza-bicyclo[3.3.1]non-2-en-1-ol structure in hand, the sub-strate scope of the reaction was next investigated(Table 10).26 A variety of 3-aryl-2-azabicyclo[3.3.1]non-2-en-1-ols were prepared in good to excellent yields; pyr-rolyl and indolyl moieties were successfully incorporatedinto the corresponding products (entries 8 and 9, respec-tively). The steric hindrance in a,b-disubstituted vinylazide 62 made its reaction sluggish, giving the desiredcompound 205 in only 28% yield along with the recoveryof 62 (68%), even in the presence of 40 mol% of the cat-alyst (entry 10). The introduction of substituents, such asalkyl, vinyl, and phenyl groups, at C-4 of the bicyclic cy-clopropanol did not retard the reaction and provided thecorresponding 2-azabicyclo[3.3.1]non-2-en-1-ols in highyields and with good diastereoselectivity (exo-selective,83:17 to 94:6) (entries 11–15). In these cases, the additionof the b-carbonyl radicals to vinyl azide 32 in the carbon–carbon bond formation occurred in an anti-selective man-ner with respect to the adjacent C-4 substituents to mini-mize 1,2-steric repulsion.

Having prepared the 2-azabicyclo[3.3.1]non-2-en-1-ols,we then explored their transformation into 2-azabicy-clo[3.3.1]nonane (morphan)27 or 2-azabicyclo[3.3.1]non-2-ene frameworks, which are prevalent in several naturalalkaloids as well as biologically active molecules.35

The treatment of 196 with sodium cyanoborohydride(NaBH3CN) in the presence of HCl induced the doublehydride reduction of the carbon–nitrogen double bond andcarbon–oxygen bond, affording 2-azabicyclo-[3.3.1]nonane 216 stereoselectively in 70% yield(Scheme 13).26a The first hydride attacked the carbon–nitrogen double bond entirely from the less-hindered exo-face to form hemiaminal I. Subsequent dehydration of Igave the bridgehead iminium species II, which could bereduced by one more hydride to afford product 216.

Scheme 13

A one-pot conversion could be achieved starting from vi-nyl azide 32 and cyclopropanol 195 using Mn(acac)3 as acatalyst followed by treatment with NaBH3CN (3 equiv)and HCl (3 equiv). Product 216 was formed in good yieldwithout the isolation of 2-azabicyclo[3.3.1]non-2-en-1-ol

Scheme 11

+N

Mn(acac)3 (10 mol%)

EtOH, r.t., 5 minunder N2

HO OEt

188(1.2 equiv)

OEt

NH O

R

NaBH4(2 equiv)

NH

OR

190: R = H; 85%191: R = 4-Br; 80%192: R = 4-CO2Me; 69%193: R = 4-Me; 81%194: R = 4-OMe; 87%

R

N2

+Mn(acac)3 (5 mol%)

MeOH, r.t., 1 h(slow addition of 195

through a syringe pump)32

N195

(85% ee)(1.2 equiv)

OHPh

Ph

NNN

[MnIII]

[MnII], H+

N2

195

32

H+O

O

196

I

• A proposed catalytic cycle

O

N

Ph

H[Mn(III)]

II-ax

III

NOH

HPh

NO[MnIII]

HPh

OH

Ph

N

[Mn(III)]

[MnII]

II-eq

N2196 89% (0% ee)

NaBH3CN (3.0 equiv)HCl in MeOH (3 equiv)

MeOH, r.t., 2 h

196

216 70%

N

OH

H

N

H

H

HH

H+N

OH

HPh

HH–

NPh

H

H

OHH

NPh

H

H

OH2H

H+

NPh

H

H

H

H–

216–H2O

• A proposed reaction pathway

I

II

196

Dow

nloa

ded

by: U

nive

rsity

of O

xfor

d. C

opyr

ight

ed m

ater

ial.



196. This one-pot/two-step process represents a straight-forward procedure for the construction of the morphanframework from readily available vinyl azides and bicy-clic cyclopropanols (Table 11).26a

Further methods for the reduction of the carbon–oxygenbond at the bridgehead position were explored using ace-tate 224 prepared from alcohol 196 (Scheme 14).26 Inter-estingly, the titanium(IV) chloride (TiCl4) mediated

reduction of acetate 224 with triethylsilane induced selec-tive carbon–oxygen bond cleavage, affording 2-azabicy-clo[3.3.1]non-2-ene 225 in 90% yield, keeping thecarbon–nitrogen double bond intact. Similarly, treatmentwith trimethylaluminum or allyltrimethylsilane–TiCl4

provided a new quaternary carbon center36 at the bridge-head position, giving products 226 and 227, respectively.These transformations might proceed via a bridgeheadcarbocation,37 which is then immediately trapped by thecorresponding nucleophile.

Scheme 14

Melinonine-E (228) has been isolated from the bark ofStrychnos melinoniana,38 and its structure is characterizedby a unique pentacyclic ring system including indolo[2,3-a]quinolizidine and morphan frameworks.39 The first syn-thesis of (±)-melinonine-E (228) was accomplished byBonjoch and co-workers.40 We envisaged that the 2-aza-bicyclo[3.3.1]nonane moiety of melinonine-E (228) couldbe constructed by the Mn(III)-mediated [3+3]-annulation

Table 10 Manganese(III)-Catalyzed Synthesis of 2-Azabicy-clo[3.3.1]non-2-en-1-olsa

a Unless otherwise noted, the reactions were carried out by the addi-tion of a solution of the cyclopropanol (1.2 equiv) in MeOH, via a sy-ringe pump over 1 h, to a solution of the vinyl azide (0.3 mmol) and Mn(acac)3 (10 mol%) under a N2 atmosphere at r.t.b Isolated yields unless otherwise noted.c 5 mol% of Mn(acac)3 was used.d 40 mol% of Mn(acac)3 was used.e Vinyl azide 62 was recovered in 68% yield.f The ratio was determined by 1H NMR spectroscopy, and the major exo-isomer is shown.g The structures of exo-isomers 205, 209, and 213 were secured by X-ray crystallographic analyses.h NMR spectroscopic yield, using Cl2CHCHCl2 as an internal stan-dard, owing to the instability of 211; this product could be isolated as its acetate in 73% yield on treatment of the crude mixture of 211 with Ac2O (8.0 equiv), Et3N (2.0 equiv), and DMAP (0.1 equiv) in CH2Cl2 at r.t. for 8 h.

Entry Yield/%bVinyl azides Cyclopropanols

N

R


1 89c

95195195195195195195195

88

708375

234567

8

93

9d

52N

TsN

50

N

TsN

10d 62N

Me

1314

1112

OH

R

N

OH

H

Products

OH

R

196197198199200201202

N

OH

HNTs

N

OH

HNTs

195

195

203 83c

204 77c

195 28d,eN

OH

H

Me

H

205

(exo/endo = 85:15)f,g

207: 90 (exo/endo = 85:15)f

N

OH

H

R

HN

32 206: R = i-Pr208: R = CH=CH2210: R = CH2CH=CH2212: R = Ph214: R = CH2OMOM15

32323232

209: 82 (exo/endo = 83:17)f,g

211: 86 (exo/endo = 86:14)f,h

213: 91 (exo/endo = 94:6)f,g

215: 74 (exo/endo = 85:15)f

N2

N2

N2

N2

N2

Table 11 One-Pot Synthesis of 2-Azabicyclo[3.3.1]nonanesa,b

a The reactions were carried out by the addition of a solution of the cyclopropanol (1.2 equiv) in MeOH, via a syringe pump over 1 h, to a solution of the vinyl azide (0.3 mmol) and Mn(acac)3 (10 mol%) un-der a N2 atmosphere at r.t.; this was followed by treatment with NaBH3CN (3 equiv) and HCl in MeOH (3 M, 3 equiv) for 3 h.b Isolated yields are shown next to the corresponding products.c The ratio of the exo- and endo-isomers was determined by 1H NMR spectroscopy, and the major exo-isomer is shown.

+

Mn(acac)3(10 mol%)

MeOH, r.t.N(1.2 equiv)

R1 OH

R2

NaBH3CN(3 equiv)

HCl in MeOH(3 equiv)

N

H

H

HH

R1R2

N

H

H

HH

R1

70% (32+195)216: R1 = H217: R1 = 4-Me 68% (34+195)218: R1 = 4-OMe 58% (36+195)219: R1 = 4-Br 76% (40+195)

220: R2 = CH(CH3)2 70% (85:15)c (32+206)221: R2 = CH=CH2 67% (81:19)c (32+208)222: R2 = CH2CH=CH2 80% (81:19)c (32+210)223: R2 = Ph 56% (90:10)c (32+212)

N

H

H

HH

R2

N2

a. Ac2O 86%

224

b. TiCl4 Et3SiH 90%

225

226

d. TiCl4

82%

c. Me3Al 83%

227TMS

196

N

OH

H

N

OAc

H

NH

H

NMe

H

N

H

A proposed mechanism

224

225–227

N

O

HPh

Me

OLA

N

HPh

LA

AcO

N

Nu

HPh

Lewis acids(LA)

Nu–

Dow

nloa

ded

by: U

nive

rsity

of O

xfor

d. C

opyr

ight

ed m

ater

ial.

32 S. Chiba ACCOUNT


of vinyl azide 50 and a bicyclic cyclopropanol bearing ahydroxymethyl-type tether, followed by the reduction ofthe carbon–nitrogen double bond and bridgehead carbon–oxygen bond in intermediate II to give I (Scheme 15).The construction of the C-ring of melinonine-E (228) wasplanned at a later stage.

Scheme 15

[3+3]-Annulation of 1-indol-2-ylvinyl azide (50) and bi-cyclic cyclopropanol 229 afforded azabicyclic compound230 in 88% yield on a 2-gram scale in a diastereoselectivemanner (exo/endo = 85:15), although 1.6 equivalents ofMn(acac)3 were needed to complete the reaction(Scheme 16).26a After the conversion of alcohol 230 intoits acetate, the bridgehead carbon–oxygen bond was re-duced using the Et3SiH–TiCl4 protocol to afford cyclicimine 231. Subsequent reduction of the carbon–nitrogendouble bond of 231 with lithium aluminum hydride–alu-minum trichloride41 led to not only the entire reduction ofthe imine and N-tosyl moieties, but also partial removal ofthe tert-butyldiphenylsilyl (TBDPS) group. Reductive N-alkylation of the resulting secondary amines of 232 withdimethoxyacetaldehyde in the presence of sodium triacet-oxyborohydride provided 233 and 234 in 43 and 12%yield, respectively. The remaining TBDPS group in 233was removed with tetrabutylammonium fluoride. Borontribromide induced cyclization of 234 proceeded cleanlyto afford cyclic alcohol 235, which underwent dehydra-tion with maleic acid in water followed by dehydrogena-tion with palladium black in a one-pot manner42 to afford(±)-melinonine-E (228) as a perchlorate salt in 44% yieldfrom 234. The 1H and 13C NMR spectroscopic data of thesynthetic (±)-melinonine-E perchlorate were identical tothose previously reported.39,40a

2.4 Synthesis of Isoquinolines from a-Aryl-Sub-stituted Vinyl Azides and Internal Alkynes by Rhodium–Copper Bimetallic Cooperation

As mentioned in Section 2.1, vinyl azides readily undergothermal denitrogenation to afford highly strained three-membered cyclic imines, 2H-azirines, which can be re-garded as vinylnitrene equivalents (Scheme 17). Weturned our attention to the use of these nitrogen atoms de-rived from a-aryl-substituted vinyl azides to direct a metalcomplex for ortho C–H metalation,43 which might be fol-lowed by a carbon–carbon and carbon–nitrogen bond for-

mation sequence with internal alkynes to constructazaheterocyclic frameworks.

It has been revealed that the combined use of [Cp*RhCl2]2

(Cp* = pentamethylcyclopentadienyl) and metal acetatesgenerates Cp*Rh(OAc)n species and results in deprotona-tive carbon–hydrogen bond cleavage with the aid of an in-tramolecular directing group, such as an imino group, toafford rhodacycles.44,45 The application of this strategy forthe synthesis of various kinds of heterocycles has beenstudied using reactions with internal alkynes.46,47 Basedon these background reports, we embarked on our inves-tigation of the reaction of 1-phenylvinyl azide (32) anddiphenylacetylene (236) using [Cp*RhCl2]2 as a catalyst

N

H

HOH

H

melinonine-E 228

C-ring construction

50

N3

TsN

OH

OR

+Mn(III)

NH

A BDC E

NOH

HNTs

A B D E OR

N

H

H

HH

ORNTs

A BD E

I

II

[3+3]-annulation

Scheme 16 Synthesis of (±)-melinonine-E (228); reagents and con-ditions: (a) 229 (3.0 equiv, added by a syringe pump), Mn(acac)3 (1.6equiv), MeOH, r.t., 8 h, 88% yield; (b) Ac2O (8.0 equiv), Et3N (2.0equiv), DMAP (0.1 equiv), CH2Cl2, r.t., 12 h, 87% yield; (c) TiCl4

(1.5 equiv), Et3SiH (2.0 equiv), CH2Cl2, r.t., 4 h, 83% yield; (d) AlCl3

(5.0 equiv), LAH (15.0 equiv), r.t., 30 h; (e) (MeO)2CHCHO (1.5equiv), NaB(OAc)3H (1.5 equiv), CH2Cl2, 0 °C, 30 min, 43% yield of233 + 12% yield of 234 (both from 231); (f) TBAF (1.5 equiv), THF,r.t., 36 h, 93% yield; (g) BBr3 (8.0 equiv), CH2Cl2, –78 °C, 3 h; (h)maleic acid (6.0 equiv), H2O, r.t., overnight, then Pd black (excess),reflux, 50 h; aq NaClO4 (3.0 equiv), r.t., 44% yield (from 234)

50

N3

TsN

OH

OTBDPS

229

+a. Mn(acac)3

88%

230(exo:endo = 85:15)

b. Ac2O (87%)

c. TiCl4, TES (83%) 231

d. LAH, AlCl3

232 (R = TBDPS or H)

e. MeO CHO

MeO

233: R = TBDPS; 43% (from 231)

234: R = H; 12% (from 231)f. TBAF 93%

g. BBr3

235

h. maleic acid, H2O then Pd black

then aq NaClO4 44% (from 234)

melinonine-E 228

N

OH

HNTs

OTBDPS

N

H

HNTs

OTBDPS

N

H

H

HH

ORNH

N

H

H

ORNH

MeO

MeO

N

H

HOH

HNH

HO

H

ClO4–

N

H

HOH

HNH

NaB(OAc)3H

Scheme 17

N

R

2H-azirines

R'R

N

N2

vinyl azidesR'

– N2R

N

R'vinylnitrenes

–Can these nitrogens (N) direct a metal complex to the proximal C–H bond for ortho metallation?–

Δ

Dow

nloa

ded

by: U

nive

rsity

of O

xfor

d. C

opyr

ight

ed m

ater

ial.



with carboxylate sources (Table 12) to target isoquinolinederivatives.48 While the use of sodium acetate (NaOAc) orcesium pivalate (CsOPiv) (30 mol%) as a carboxylatesource did not afford any ortho carbon–hydrogen bondfunctionalization product (entries 1 and 2, respectively),the reaction with copper(II) acetate [Cu(OAc)2] (20mol%) at 110 °C in N,N-dimethylformamide (DMF) gave1-methyl-3,4-diphenylisoquinoline (237) in 70% yield(entry 3). The addition of 1 equivalent of AcOH allowedfor a lower reaction temperature (90 °C) and catalyticloading of [Cp*RhCl2]2 (2.5 mol%) (entries 5 and 6). No-tably, an acceleration of the reaction rate was observed us-ing copper(I) acetate (CuOAc) instead of Cu(OAc)2 (entry7).

Using the [Cp*RhCl2]2 (5 mol%)–Cu(OAc)2 (20 mol%)catalytic system, the generality of this method was exam-ined for the synthesis of substituted isoquinolines and oth-er derivatives (Table 13).48 Wide substrate tolerance wasobserved with the use of internal alkynes (entries 1–8).The reactions with diarylacetylenes proceeded smoothlywith vinyl azide 32, giving isoquinolines in good yields(entries 1–3). Dialkylacetylenes also resulted in reason-ably smooth reactions (entries 4 and 5). The insertion ofunsymmetrical 1-phenylprop-1-yne (248) occurred in aregioselective manner, affording 1,4-dimethyl-3-phenyl-isoquinoline (249) as the sole product (entry 6). Similarly,methyl 3-phenylpropanoate (250) and 1-(2-thienyl)oct-1-yne (252) provided isoquinolines 251 and 253 regioselec-tively, albeit in lower yields (entries 7 and 8, respective-ly). The introduction of electron-withdrawing groups assubstituents on the benzene ring of the a-aryl-substitutedvinyl azide resulted in isoquinoline formation in goodyields, whereas sluggish reactions were observed from vi-nyl azide 36, bearing the electron-donating methoxy moi-ety (entry 10), as well as from 1-(1-naphthyl)vinyl azide(48) (entry 14). Carbon–bromine bonds could be kept in-tact in the synthetic process (entries 3, 12, and 15). Regio-

isomeric mixtures were obtained in the reactions of meta-substituted substrates, where the less sterically hinderedcarbon–hydrogen bond was cleaved in a preferential man-ner (marked in blue) (entries 15 and 16). The constructionof b-carboline, 1H-pyrrolo[2,3-c]pyridine, benzofuro-[2,3-c]pyridine, and benzothiopheno[3,2-c]pyridinestructures could be achieved using the above process (en-tries 17–20, respectively). The introduction of methyl, sil-oxymethyl, alkoxymethyl, and aminomethyl groups at theb-position of the vinyl azide did not retard the process andled to the corresponding isoquinolines in moderate togood yields (entries 21–26).

To probe how both the rhodium and copper catalysts workin the reaction mechanism, several control experimentswere conducted using vinyl azide 32 and alkyne 236(Scheme 18).48

The incorporation of deuterium into the methyl group ofthe isoquinoline product to give 279 was observed in thereaction conducted in the presence of water-d2 (D2O) (5equiv) (Scheme 18, part a), whereas this was not observedin the reaction using DMF-d7 as a solvent.49 These resultssuggest that the hydrogen atom at the resulting methylmoiety is introduced not via a radical pathway, but in anionic manner.

Next, 2H-azirine 280, prepared by the thermal decompo-sition of vinyl azide 32, was subjected to the reaction withalkyne 236 in the presence of [Cp*RhCl2]2 and metal ace-tates. The reaction with Cu(OAc)2 or CuOAc affordedisoquinoline 237; no isoquinoline formation was seenwith NaOAc at all (Scheme 18, part b). Moreover, the re-action with CuOAc was completed within 10 minutes,whereas that of Cu(OAc)2 needed 2 hours. The reaction ofvinyl azide 32 with 2 equivalents of CuOAc in the pres-ence of AcOH gave acetophenone (282) in 48% yield,presumably via hydrolysis of the putative N-unsubstituted(N-H) imine 281 (Scheme 18, part c). Interestingly, the re-action with [Cp*RhCl2]2–Cu(OAc)2 under an oxygen at-mosphere did not afford isoquinoline 237. In sharpcontrast, a carbon monoxide atmosphere promoted theisoquinoline formation to give the product in 82% yieldwithin 0.5 hours (Scheme 18, part d).

These experimental results indicated that both rhodium(Rh) and copper (Cu) are indispensable for inducing theortho carbon–hydrogen bond functionalization of 2H-azirine 280 in the reaction to give product 237. The lowervalent Cu(I) species might take part in the reductive ringopening of the 2H-azirine to give the imine derivative,50

which then might be relayed to initiate Rh(III)-catalyzedortho C–H rhodation, followed by insertion of the alkyne.In fact, the ultraviolet/visible (UV/vis) spectra for thetreatment of Cu(OAc)2 in DMF at 90 °C showed quench-ing of the visible band of Cu(OAc)2 at 700 nm. This ob-servation suggests that a solvent amount of DMF mightreduce Cu(OAc)2 to form the Cu(I) species.51 The UV/visspectra for the treatment of [Cp*RhCl2]2 in DMF at 90 °Cshowed no change of the visible band of [Cp*RhCl2]2 at410 nm.

Table 12 Optimization of the Reaction Conditions for the Synthesis of Isoquinoline 237a

a All reactions were carried out using 0.5 mmol of alkyne 236 with 1.2 equiv of vinyl azide 32 under a N2 atmosphere.b Isolated yields, unless otherwise noted, based on alkyne 236.c NMR spectroscopic yield.

NN2

32 (1.2 equiv)

+ Ph Ph

236

cat. [Cp*RhCl2]2additive-1additive-2

DMF, conditions

NPh

Ph

Me

237

Entry Yield/%b[Cp*RhCl2]2/mol%

Additive-1/mol% Conditions

1

2

3

7

5

Additive-2/mol%

5 NaOAc (30) 110 °C, 12 h 0

5 CsOPiv (30) 110 °C, 12 h 0

5 Cu(OAc)2 (20) 110 °C, 0.3 h 70

4 5 Cu(OAc)2 (20) 90 °C, 1 h 67cH2O (100)

5 Cu(OAc)2 (20) 90 °C, 0.6 h 80AcOH (100)

2.5 Cu(OAc)2 (20) 90 °C, 2 h 84AcOH (100)2.5 CuOAc (20) 90 °C, 0.5 h 84AcOH (100)

6

Dow

nloa

ded

by: U

nive

rsity

of O

xfor

d. C

opyr

ight

ed m

ater

ial.

34 S. Chiba ACCOUNT


Based on these experimental data, a possible mechanismunder the [Cp*RhCl2]2–Cu(OAc)2 catalytic system wasproposed, as outlined in Scheme 19. First, the Cu(I) spe-cies is formed via the reduction of Cu(OAc)2 by DMF(step i). 2H-Azirine 280, generated by thermal denitroge-native decomposition of vinyl azide 32, is reduced by theCu(I) species to afford radical anion A (step ii, path a).Ring opening by carbon–nitrogen bond cleavage of Aforms iminylcopper(II) radical intermediate B, which isfurther reduced with Cu(I) and protonated to give N-Himine 281 along with the Cu(II) species. Alternatively, itcan be proposed that the direct reduction of vinyl azide 32by the Cu(I) species forms the putative radical intermedi-ate B via vinyl azide radical anion E (step ii, path b). Theformation of rhodacycle G from N-H imine 281 or iminyl-copper intermediate D with Rh(III) via iminyl rhodium F,followed by insertion of alkyne 236 and subsequent car-bon–nitrogen bond formation through reductive elimina-tion from H, provides isoquinoline 237 with thegeneration of the Rh(I) species (step iii). Finally, a redoxreaction between the Rh(I) and Cu(II) species leads to theregeneration of Rh(III) and Cu(I) (step iv).

The reductive formation of imine derivatives from vinylazides is supposed to proceed via the protonation of cop-per(II) azaenolates, such as C (Scheme 19, step ii). Weaimed to trap such putative azaenolates with other electro-philes for the further functionalization of isoquinoline de-rivatives. After the extensive screening of variouselectrophiles, it was found that the addition of TEMPO(2,2,6,6-tetramethylpiperidin-1-yloxyl) (2 equiv) insteadof AcOH in the reaction of vinyl azides 62 and 277 withseveral alkynes under the [Cp*RhCl2]2–Cu(OAc)2 cata-lytic system delivered isoquinoline–TEMPO adducts and

Table 13 Synthesis of Substituted Isoquinolines and Other Deriva-tives from a-Aryl-Substituted Vinyl Azides and Internal Alkynes Cat-alyzed by [Cp*RhCl2]2–Copper(II) Acetatea

a The reactions were carried out by treating a mixture of the vinyl azide (1.2 equiv) and alkyne (0.5 mmol) with [Cp*RhCl2]2 (5 mol%) and Cu(OAc)2 (20 mol%) in the presence of AcOH (1 equiv) in DMF (2.5 mL) at 90 °C under a N2 atmosphere for 1–2 h.b Isolated yields unless otherwise noted.c 1.5 equiv of vinyl azide 32 were used.d NMR spectroscopic yield.e 2.5 mol% of [Cp*RhCl2]2 was used.f 10 mol% of [Cp*RhCl2]2 was used.

R2R1

Entry Vinyl azides Alkynes Isoquinolines / yieldb

1

67

4

NR1

R2

Me2

32 239: 77%238 (R1, R2 = 4-MeOC6H4)

32 248 (R1 = Me, R2 = Ph) 249: 82%32 250 (R1 = CO2Me, R2 = Ph) 251: 27%

32 244 (R1, R2 = n-Pr) 245: 71%5 32 246 (R1 = CH2OTBS, R2 = CH2OTBS) 247: 54%

34 (R = Me) 236

NPh

Ph

Me

R254: 80%

NN2

2 32 241: 70%240 (R1, R2 = 4ClC6H4)3c 32 243: 83%242 (R1, R2 = 4-BrC6H4)

8 32 252 (R1 = n-hexyl, R2 = 2-thienyl) 253: 52%d

NN2

R PhPh

36 (R = OMe) 236 255: 45%d

44 (R = CO2Me) 236 256: 86%40 (R = Br) 236 257: 80%

91011e

12

NPh

Ph

Me

R

NPh

Ph

MeR

261: 74% 262: 12%15

NN2

R23642 (R = Br)

82 (R = NO2)16 236 263: 66% 264: 5%

258 236N

PhPh

Me 259: 70%

NN2

13

Me Me

17 236NTs

N

Ph Ph

Me50

265: 82%

18 236NTs

N

Ph Ph

Me52

266: 77%

NN2

Me

R2R1

21e 62 270: 85%236 (R1, R2 = Ph)22e 62 271: 54%244 (R1, R2 = n-Pr)23e 62 272: 80%248 (R1 = Me, R2 = Ph)

NR2

R1

Me

N

OR

N2

N

N

N2

24

26

273 (R = TBDPS)275 (R = CH2CH=CH2)

236 NPh

Ph

OR

274: 46%

O

O 277 236

NPh

Ph

N

O

O

278: 85%

25 236 276: 40%

236O

N

Ph Ph

Me267

S

N

Ph

Ph

Me

S

N N2 236

14 23648 260: 38%

19f

20

268: 45%

54269: 75%

NN2 NMe Ph

Ph

NTs

NN2

NTs

NN2

ON

N2

Scheme 18

N

N2 [Cp*RhCl2]2 (2.5 mol%)Cu(OAc)2 (20 mol%)

D2O (5 equiv)

DMF, 90 °C, 3.5 h+ Ph Ph CDnH3–n

NPh

Ph

32236

279 60%

(n = 1.62)(a)

[Cp*RhCl2]2 (2.5 mol%)Cu(OAc)2 (20 mol%)

AcOH (1 equiv)

DMF, 90 °Catmosphere

Me

NPh

Ph

0%

+32 236

32toluene

100 °C, 1.5 h82%

(NMR yield)

N

280 (1.2 equiv)

236 (1.0 equiv)[Cp*RhCl2]2 (5 mol%)M(OAc)n (20 mol%)

AcOH (1 equiv)

DMF, 90 °Ctime

Me

NPh

Ph

237M(OAc)n

NaOAc

Cu(OAc)2

0%

46%CuOAc 52%

time

2 h

2 h10 min

(b)

(d)

CuOAc (2 equiv)AcOH (2 equiv)

DMF, 90 °C

Me

O

282 48%

(c)Me

NHN

N2

32

under O2under CO (0.5 h) 82%

237

281

Dow

nloa

ded

by: U

nive

rsity

of O

xfor

d. C

opyr

ight

ed m

ater

ial.



alcohols in good combined yields (Table 14).48,52 From vi-nyl azide 277, a b-amino alcohol unit could be installed inthe isoquinoline framework (entry 4). Although we arenot certain as to the reaction mechanism of this carbon–oxygen bond formation, one possibility might be the nu-cleophilic attack of the azaenolate carbon to a Cu(II)–TEMPO complex, which would act as an ionic electro-phile.

3 Chemistry of Cyclic 2-Azido Alcohols

3.1 Manganese(III)-Catalyzed Ring Expansion of 2-Azidocyclobutanols

Following the above-mentioned formal [3+2]- and [3+3]-annulation strategies of vinyl azides via an iminylmanga-nese(III) species as a key intermediate, we planned an al-ternative method for generating such metal species usingthe metal-mediated b-fission (b-carbon elimination) ofcyclic 2-azido alcohols.53 As shown in Scheme 20 as anexample, the oxidative b-fission of 2-azidocyclobutanolor -cyclopentanol would provide iminyl radical/metalspecies along with the formation of an intramolecular car-bonyl moiety, which would cyclize to afford the corre-sponding heterocycles, such as pyrrole (n = 1) or pyridine(n = 2), respectively.

As expected, the catalytic conversion of 2-azidocyclobu-tanols proceeded smoothly with Mn(pic)3 to give the cor-responding pyrroles 291–293 in excellent yields,54

whereas that of 2-azidocyclopentanol or -cyclopentenolderivatives was unsuccessful (Scheme 21).55 This sug-gested that the release of the ring strain is indispensable asa key driving force of this Mn(III)-catalyzed b-fissionstrategy.

Scheme 21

3.2 Palladium(II)-Catalyzed Ring Expansion of Cyclic 2-Azido Alcohols

Further extensive investigations revealed that a palladi-um(II) [Pd(II)] catalyst system could achieve the ring-ex-pansion reaction of nonstrained cyclic 2-azidopentenolderivatives.56 The reaction involves an unprecedented car-bon–carbon bond cleavage57 and carbon–nitrogen bondformation sequence to provide azaheterocycles, such aspyridine and isoquinoline derivatives.

Scheme 19

[RhIII]N

Me

[RhIII] N

Me

[RhIII]Ph

Ph

281 or D

G

– [RhI]

(iii) ortho C–H rhodation, alkyne insertion, and C–N reductive elimination

236

[RhI] 2 [CuII]+ [RhIII] + 2 [CuI]

– H+ or – Cu(II)

(iv) redox regeneration of the Rh(III) and Cu(I) species

CuII(OAc)2 +

(i) generation the of Cu(I) species by reduction of Cu(OAc)2 with DMF

(ii) reductive formation of NH imines from vinyl azides and the Cu(I) species

Ph

Ph

H237

[Rh] = Cp*Rh(OAc)n

[CuI]

Ph

N

N2

– N232 280 281

Ph

N [CuI]

[CuI]

Ph

N

[CuII]

[CuII]

Cpath b

path a

Ph

N [CuII]

Ph

N

N2 [CuII]

[CuI]

– N2 Ph

N

[CuII]

B

A

EPh

N

Me

[CuII]

D

H+

– [CuII]

H+ [CuII]

N

Me

[RhIII]

F

H

– H+

Ph

NH

Me

H N

OMe

Me (DMF)

Scheme 20

OH

N N Nn

O

N N Nn

O

N N Nn

O

Nn

NH N

(n = 1) (n = 2)

or

[Mn]

– [Mn–1]

– N2

Table 14 Reaction of Vinyl Azides and Internal Alkynes with 2,2,6,6-Tetramethylpiperidin-1-yloxyla

a All reactions were carried out using 0.5 mmol of the alkyne with 1.5 equiv of the vinyl azide under a N2 atmosphere.b Isolated yields are shown based on the alkyne.

N

N2[Cp*RhCl2]2 (2.5 mol%)

Cu(OAc)2 (20 mol%)

DMF, 90 °C, 1 h+ R2 R3

(1.5 equiv)R1

NO

+

(2 equiv)

NO

R1

R2R3

N NOH

R1

R2R3

+

N

N

N2

O

O

277

Entry Vinyl azides AlkynesTEMPO adductsb Alcoholsb

283: 68% 284: 15%

285: 39% 286: 42%

287: 55% 288: 18%

289: 48% 290: 29%

1

2

3

4c PhPh

236

NN2

Me

PhPh236

n-Prn-Pr244

PhMe62

248

TEMPO adducts alcohols

NHO

R

(10 mol%)

MeOH, 0 °C, 0.5 hthen 40 °C, 3 h

NHR

291 (R = H); 90%292 (R = Me); 88%293 (R = Cl); 89%

N

O OMn

3

N

OHMn(III)

no reactionN

0%

N2

N2

Dow

nloa

ded

by: U

nive

rsity

of O

xfor

d. C

opyr

ight

ed m

ater

ial.

36 S. Chiba ACCOUNT


As a model substrate, (1R*,5R*)-5-azido-2,3-diphenylcy-clopent-2-enol (trans-294) was selected, and its reactionsunder Pd catalyst systems (with 1 equiv of K2CO3 inDCE) were examined.56 While Pd(II) complexes them-selves did not exhibit any reactivity, they showed interest-ing catalytic effects in the presence of phosphine andnitrogen ligands, giving the ring-expansion product 3,4-diphenylpyridine (295) (Scheme 22). Extensive ligandscreening revealed that bidentate ligands worked effi-ciently with Pd(II) catalysts for the pyridine formation,and the use of PdCl2(dppf) [dppf = 1,1¢-bis(diphenylphos-phino)ferrocene] (15 mol%) at 80 °C gave 295 in the bestyield (88%). Interestingly, Pd(OAc)2 with bidentate nitro-gen ligand 2,2¢-bipyridine also exhibited good catalyticactivity. The reactions of the corresponding cyclic cis-2-azido alcohol cis-294 also proceeded to form pyridine295, although the yield of 295 was lower than that fromtrans-294. It was also noted that other metal complexes,such as nickel(II), Cu(I), Rh(I), and gold(I) complexes,were not viable catalysts for this transformation.

Scheme 22 Optimized reaction conditions for the palladium-cataly-zed ring expansion of cyclic 2-azido alcohols

As shown in Scheme 23, the catalytic cycle could be ini-tiated by b-carbon elimination of palladium(II) alcoholateI, generated from azido alcohol 294 with a Pd(II) complexin the presence of a base. It was speculated that this pro-cess might be promoted by the coordination of the internalnitrogen of the azido moiety to the metal center.58 Thesubsequent elimination of molecular nitrogen providesiminylpalladium(II) species II, which undergoes intramo-lecular nucleophilic attack to the resulting carbonyl group,affording cyclized intermediate III. Protonation of III fol-lowed by dehydration affords pyridine 295 along with thePd(II) complex. Alternatively, elimination of a hydroxi-dopalladium(II) species from III provides 295 directly.

The generality of this catalytic ring expansion for the syn-thesis of substituted pyridines was next examined usingtrans-azido alcohols (Table 15).56 The method allowedthe installation of not only aryl substituents, but also me-thyl and allyl groups at C-3 of the pyridine ring. 3,4-Di-alkyl-substituted pyridine 302 could also be synthesizedin good yield. Importantly, 3-chloro- and 3-bromopy-ridines 303 and 304 could be prepared with the carbon–

chlorine and carbon–bromine bonds, respectively, intact.3-Arylpyridines with some substituents were available us-ing this method.

This catalytic ring expansion could be applied to the syn-thesis of substituted isoquinoline derivatives from the cor-responding azidoindanols (Table 16).56 It should be notedthat the reactions of both trans-1-azidoindan-2-ol andtrans-2-azidoindan-1-ol derivatives afforded the sameisoquinolines. Interestingly, the reactions of the 2-azido-indan-1-ol derivatives, such as 312 and 315, proceeded atroom temperature using a Pd(OAc)2–dppf system to givethe products in excellent yields. Both electron-withdraw-ing and electron-donating groups were incorporated onthe isoquinoline ring. Chloro substituents on the benzenering were tolerated. Azido alcohols bearing a phenylgroup at C-3 or C-2, such as in 322 and tertiary alcohol324, respectively, were converted into the correspondingisoquinolines in good yields. Moreover, this method alsoafforded g-carboline 327 from substrate 326.

Pd catalyst, ligand K2CO3 (1 equiv)

DCE80 °C

Ph

Ph

OH

N3

NPh

Ph

trans-294 295

Ph

Ph

OH

N3

cis-294

Pd(OAc)2–2,2'-bipyridine (15 mol%), 0.5 h 80%PdCl2(dppf) (15 mol%), 5 h 88%

PdCl2(dppf) (15 mol%)K2CO3 (1 equiv)

DCE80 °C, 4 h

NPh

Ph

295 59%

Scheme 23

[PdII]294

Ph

Ph

OH

N N N

I

Ph

Ph

O

N N N

[PdII]

II

Ph

Ph

O

N

[PdII]III

NPh

Ph

O[PdII]

H2O IV

NPh

Ph

OH

NPh

Ph

N2

295

H+

[PdII]–OH

H+

Table 15 Synthesis of Pyridines from Cyclic 2-Azido Alcoholsa,b

a Unless otherwise noted, the reactions were carried out using 0.3 mmol of the azido alcohol in the presence of 15 mol% of PdCl2(dppf) and 1 equiv of K2CO3 in DCE (2 mL) at 80 °C under a N2 atmosphere.b Isolated yields are shown next to the corresponding products.c The reaction was run using 10 mol% of Pd(OAc)2 and 2,2¢-bipyri-dine as a catalyst.d 20 mol% of PdCl2(dppf) was used.

R1

R2

OH

N3

NR1

R2

296; R = Me: 78%297; R = Cl: 88%298; R = F: 89%

N

RN

Me

299: 83%

NMe

Me

Me

300: 74%

N

301: 80%

NMe

302: 65%

NX

303; X = Cl: 90%304; X = Br: 72%c

305; R = H: 83%d

306; R = Me: 64%307; R = Cl: 84%308; R = F: 86%309; R = CF3: 93%

N

R

PdCl2(dppf) (15 mol%)K2CO3 (1 equiv)

DCE80 °C

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4 Chemistry of a-Azido Carbonyl Compounds

4.1 Orthogonal Synthesis of Isoindole and Iso-quinoline Derivatives

Isoindoles and their derivatives are attractive candidatesfor organic light-emitting devices (OLEDs) owing to theirgood fluorescent and electroluminescent properties.59

They show high reactivity in [4+2] cycloadditions withvarious dienophiles for the preparation of oligoacenes.60

We envisaged that the intramolecular azide–alkene cy-cloaddition reaction61 of readily available a-azido carbon-yl compound 328, bearing a 2-alkenylaryl moiety at the a-position, and the subsequent elimination of molecular ni-trogen from the resulting triazoline would produce isoin-dole 329, as shown in Scheme 24.

The expected isoindole formation proceeded smoothly onheating azide 328 in toluene (0.1 M concentration) at 100°C, giving isoindole 329 in 98% yield (Table 17, entry

1).62 The reaction could also be used to install methyl andbenzyl groups, as well as some cycloalkyl moieties and analkene tether, at the C-3 position of the isoindole (entries2–8). The reaction of azide 344 bearing a 4-toluoyl groupinstead of ethoxycarbonyl also proceeded smoothly togive 1-toluoylisoindole 345 in 85% yield (entry 9). A flu-orine or bromine atom could be introduced at the C-5 orC-4 position of the isoindole ring (entries 10 and 11, re-spectively). It is noteworthy that 6H-pyrrolo[3,4-b]pyri-dine 351 was readily accessible using this method (entry12).

Following this discovery of the formation of isoindolesvia azide–alkene 1,3-dipolar cycloaddition, it was foundthat the treatment of azide 328 with potassium carbonate(K2CO3) (5 equiv as a base) and EtOH (10 equiv as a pro-ton source) in 1,3-dimethylimidazolidin-2-one (DMI) (0.3

Table 16 Synthesis of Isoquinolines and g-Carbolinea,b

a Unless otherwise noted, the reactions were carried out using 0.3 mmol of the azido alcohol in the presence of 15 mol% of PdCl2(dppf) and 1 equiv of K2CO3 in DCE (2 mL) at 80 °C under a N2 atmosphere.b Isolated yields are shown next to the corresponding products.c The reaction was carried out using 10 mol% of Pd(OAc)2 and 10 mol% of dppf at r.t.d 20 mol% of PdCl2(dppf) was used.

trans-Azidoalcohols Products (yield/%)b

N3

OH

Ph

N

Ph

N

NTsN

Ts

OH

N3

NCl

Cl 321 (90)

Cl

Cl

N3

OH

322 323 (73)

320

326 327 (93)

N3N

324 325 (62)dPhPh

OH

NO

O

O

O

X

Y

313 (X = N3, Y = OH) 314 (76)315 (X = OH, Y = N3) 314 (92)c

310 (X = N3, Y = OH) 311 (81)312 (X = OH, Y = N3) 311 (96)c

MeO2CX

YN

EtO2C

N

Cl

MeO

317 (96)cCl

MeOOH

N3

316

N

Me

Me

PhMe

Me

PhOH

N3

319 (90)318

trans-Azidoalcohols Products (yield/%)b

Scheme 24

NH

CO2Et

MeMe

N

CO2Et

NN

Me Me

– N2

CO2Et

NN

N

Me Me

isoindole 329

azide–alkenecycloaddition

N

CO2Et

N2

Me MeH

triazoline

N

CO2Et

MeMe

328

Δ

Table 17 Synthesis of Isoindole Derivatives from a-Azido Carbon-yl Compoundsa

a The reactions were carried out by heating the azide in toluene (0.1 M) at 100 °C for 3 h.b In parentheses is the two-step yield from the corresponding mesy-late. In this case, the product was obtained by treating the mesylate with NaN3 (1.2 equiv) in DMF (0.3 M) at 0 °C, followed by workup and then heating the resulting crude azide in toluene (0.1 M) at 100 °C for 3–5 h.c Z/E = 5.4:1.

331 94% (75%)

YieldbEntry

3

4

333 (99%)

CO2Et

N3NH

CO2Et

337 (87%)336 (n = 4)

IsoindolesAzides

56 339 (70%)

( )n ( )n

341 (54%)338 (n = 2)340 (n = 1)7

CO2Et

N3

MeMe

FNH

CO2Et

MeMe

34610 347 (82%)

11

CO2Et

N3

348

Br

NCO2Et

N3

MeMe

NNH

CO2Et

MeMe

350

NH

CO2Et

MeBr

349 (57%)

330 (R1, R2 = H)NH

CO2Et

R1

R2

CO2Et

N3

R2R1

332 (R1 = Ph, R2 = H)c

351 (61%)12

2

9

COp-Tol

N3

MeMe

NH

COp-Tol

MeMe

345 85%344

334 335 (87%)

F

R1 = 4-MeOC6H4 R2 = H

NH

CO2EtCO2Et

N3

328 (R1, R2 = Me) 329 98% (83%)1

8 342 343 82%

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38 S. Chiba ACCOUNT


M concentration) at 40 °C induces denitrogenation to pro-vide N-H imine 352.63 Subsequent 6p-electrocyclization64

of the resulting azahexatriene moiety of 352 was observedto be promoted by diluting the concentration with toluene(0.1 M) and heating at 100 °C, giving dihydroisoquinoline353 in 95% yield (Scheme 25, part a). Based on this find-ing, the direct transformation of mesylate 354 into dihy-droisoquinoline 353 was also achieved in 90% yield ontreatment of 354 with sodium azide (1.2 equiv), K2CO3 (5equiv), and EtOH (10 equiv) in DMI at 40 °C, followed bycyclization of the resulting imine 352 in toluene–DMI at100 °C (Scheme 25, part b).62

Scheme 25

This method resulted in the synthesis of a range of struc-turally diverse isoquinoline and dihydroisoquinoline de-rivatives from the corresponding mesylates (Table 18).62

From mesylate 355 bearing a vinyl group, the 6p-cycliza-tion followed by oxidation of the resulting dihydroiso-quinoline under an oxygen atmosphere gave ethylisoquinoline-1-carboxylate (356) in 82% yield (entry 1).The reaction of styryl derivative 357 afforded 3-phenyl-isoquinoline 358 in 52% yield along with 4-phenyliso-quinoline 359 (16% yield), which may have been formedvia rearrangement of the phenyl group during the aerobicoxidation of the dihydroisoquinoline (entry 2). However,mesylate 360 bearing a 4-methoxyphenyl group, whichhas a higher migratory aptitude than a phenyl group, gavea nearly identical distribution of products (entry 3). Dihy-droisoquinoline 364 bearing a spirocyclohexane moietywas successfully prepared in excellent yield from thecorresponding mesylate 363 (entry 4). Mesylate 365possessing a cyclobutylidenemethyl moiety gave spiro-dihydroisoquinoline 366 in 71% yield along with 13%yield of 3-propylisoquinoline 367, formed via ring open-ing of the cyclobutane moiety/aromatization (entry 5).The cyclopropane moiety, however, could not be kept inthe corresponding reaction of 368 which resulted in only3-ethylisoquinoline 369 in 88% yield (entry 6). Neitherthe replacement of the ethoxycarbonyl moiety with a4-toluoyl group nor the introduction of halogen atoms onthe aryl ring retarded the process (entries 7–9). In addi-tion, 1,7-naphthyridine framework 377 could be con-structed in good yield (entry 10). The reaction of mesylate378 bearing a 1-methylvinyl group delivered the corre-

sponding 4-methylisoquinoline 379 in 65% yield (entry11).

4.2 Generation of Iminylcopper Species and Their Catalytic Carbon–Carbon Bond Cleavage under an Oxygen Atmosphere

Based on the above-mentioned isoquinoline formation viaN-H imine intermediates, we next explored the generation

N

Me

Me

CO2Et

353 95%

K2CO3 (5 equiv)EtOH (10 equiv)

DMI (0.3 M) 40 °C, 1 h

add toluene

(0.1 M)100 °C, 8 h

NaN3 (1.2 equiv)K2CO3 (5 equiv)EtOH (10 equiv)

DMI (0.3 M) 40 °C, 1 h

add toluene

(0.1 M)100 °C, 8 h

(b)

(a)

354

imine352

CO2Et

NH

352

Me

Me

CO2Et

N

MeMe

328

CO2Et

OMs

MeMe

N

Me

Me

CO2Et353 90%

N2

Table 18 Synthesis of Isoquinoline and Dihydroisoquinoline De-rivativesa

a Unless otherwise noted, the reactions were carried out by treating the mesylate with NaN3 (1.2 equiv), K2CO3 (5 equiv), and EtOH (10 equiv) in DMI (0.3 M) at 40 °C for 1–3 h, followed by the addition of toluene (0.1 M) and then heating at 100 °C for 8 h.b After the consumption of the imine, the mixture was purged with O2 and heated at 100 °C.c Z/E = 5.4:1.

CO2Et

OMs 356 (82)355

Entry

1b

2b

CO2Et

OMs

357 (Ar = Ph)c

Isoquinolines (yield/%)Mesylate

4

N

CO2Et

N

Ar

CO2Et

5

366 (71)

364 (96)

365

363

N

CO2Et

N

CO2Et

Me

367 (13)

N

CO2EtCO2Et

OMs

CO2Et

OMs

6 369 (88)368N

CO2Et

Me

CO2Et

OMs

7 371 (78)370 N

Me

Me

COp-TolCOp-Tol

OMs

Me

Me

3728 373 (89)

9b

N

Me

Me

CO2Et

F

CO2Et

OMs374

Br

N

CO2Et

Br

375 (79)

CO2Et

OMs

Me

MeF

377 (77)376 NN

Me

Me

CO2Et

10

CO2Et

OMs379 (65)378

N

CO2Et

Me

11b

N

CO2Et

OMs

Me

Me

Me

3b 360 (Ar = 4-MeOC6H4)

358 (52) 359 (16)361 (50) 362 (14)

Ar

N

CO2Et

Ar

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of iminylmetal species by trapping N-H imine 352 withtransition metals and we looked at their chemical reactiv-ity. During the course of this study, it was found that thetreatment of N-H imine 352, generated from azide 328,with 1 equivalent of Cu(OAc)2 at 60 °C under an argon at-mosphere afforded unexpected benzonitrile 380 in 32%yield instead of isoquinoline 353 (Scheme 26).65 It wassupposed that benzonitrile 380 was formed via oxidativecarbon–carbon bond cleavage between the imino carbonand the ethoxycarbonyl carbon of the putative iminylcop-per intermediate A.

Scheme 26

The optimization of this benzonitrile formation was inves-tigated using ethyl 2-azido-2-(2-naphthyl)acetate (381)(Scheme 27).65 Treatment of 381 with Cu(OAc)2 (1 equiv)and K2CO3 (1 equiv) in DMF at 60 °C directly delivered2-naphthonitrile (382) in 78% yield along with 3% yieldof a-keto ester 383, which is likely formed by the hydrol-ysis of the corresponding iminylcopper or N-H imine in-termediate. In this case, the coordination of Cu(OAc)2 tothe internal nitrogen of the azido moiety might induce thedenitrogenative formation of the corresponding iminyl-copper. A catalytic amount of Cu(OAc)2 under an argonatmosphere could not complete the reaction. In sharp con-trast, the reaction was dramatically accelerated under aer-obic conditions. Under an oxygen atmosphere (1 atm),nitrile 382 was obtained in 90% yield using 20 mol% ofCu(OAc)2.

Scheme 27 Optimized reaction conditions for the nitrile formation

With the optimized conditions in hand, the generality ofthis catalytic method was examined for the synthesis ofcarbonitriles using a-azido esters (Table 19).65 The pro-cess provided the decarboxylated, one-carbon-shorter car-bonitriles from the corresponding carboxylic acidderivatives. The reaction allowed the installation of bothelectron-donating and electron-withdrawing groups in the

resulting arenecarbonitriles, such as in products 382–388and 389–394, respectively. Halogen atoms, such as bro-mine and fluorine, were also introduced into the productswith the reaction keeping the carbon–halogen bond intact,as in the formation of 389–392. In addition, alkanecarbo-nitriles were synthesized using sodium ethoxide as a base.In particular, the formation of tertiary carbonitriles 395and 396 proceeded in good yields, whereas the reactionsto form secondary and primary carbonitriles 397 and 398,respectively, were sluggish.

In the reaction of substrate 399 bearing a biphenyl-2-ylgroup with 40 mol% of Cu(OAc)2, benzonitrile 400 wasformed in 55% yield along with 41% yield of phenanthri-dine 401, which was presumably synthesized by carbon–nitrogen bond formation involving an aromatic carbon–hydrogen bond and a putative iminylcopper species(Scheme 28).65,66 The stoichiometric use of Cu(OAc)2 im-proved the yield of benzonitrile 400 to 74% (formed alongwith 20% yield of 401).

Scheme 28

To probe the reaction mechanism of this catalytic cyclewith a special interest in the identification of any co-prod-ucts derived from the carbonyl fragment after carbon–carbon bond cleavage and the role of the molecular oxy-

Me Me

CO2Et

N

Me Me

C380 32%

CO2Et

NH

Me

Me

K2CO3 (5 equiv)EtOH (10 equiv)

DMI, 40 °C, 1 hunder Ar

Cu(OAc)2 (1 equiv)

60 °C, 27 h

328Me Me

CO2Et

N [Cu]

352

A

N2

N

Cu(OAc)2 (1 equiv) under Ar (24 h)

Cu salts K2CO3 (1 equiv)

DMF (0.1 M), 60 °Catmosphere

CO2Et

N

381 382

+

383

CNCO2Et

ON2

78% 3%

Cu(OAc)2 (20 mol%) under O2 (7.5 h) 90% 3%Cu(OAc)2 (20 mol%) under Ar (24 h) 11% 12%

Table 19 Copper(II) Acetate Catalyzed Synthesis of Carbonitrilesa,b

a The reactions were carried out using 0.3 to 0.55 mmol of the azide.b Isolated yields are shown in parentheses next to the corresponding products.c The reactions were run by treating the corresponding bromide (for 391) or mesylate (for 392–394) with NaN3 followed by Cu(OAc)2 and K2CO3 under O2 (1 atm).d 40 mol% of Cu(OAc)2 was used at 80 °C.e A methyl ester was used as the starting material.f 1 equiv of NaOEt was used as a base.

384 (87)

CN385: R = 4-C6H5 (93%)386: R = 4-OMe (90%)

388: R = 3,4-(OMe)2

389: R = 4-Br

387: R = 2-OMe (75%)

(85%)390: R = 2-Br (47%)391: R = 3,5-Br2392: R = 3,5-F2 (49%)c

393: R = 4-CN (70%)c

394: R = 4-CO2Me (81%)c,e(72%)

(62%)c,d

R1 CO2Et

NCu(OAc)2 (20 mol%)

K2CO3 (1 equiv)

DMF (0.1 M), 60 °C under O2 (1 atm)

C NR1

arenecarbon nitriles

alkanecarbon nitrilesf

CN

Me Me

CNPh

395 (91%) 396 (64%) 397 (28%) 398 (37%)

CN

CN

382 (90)

CNR

CN

N2

N

CO2Et

399

Cu(OAc)2 K2CO3 (1 equiv)


CNN

CO2Et

400 401

+

40 mol% of Cu(OAc)2 55% 41%

100 mol% of Cu(OAc)2 74% 20%

N2

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40 S. Chiba ACCOUNT


gen, substrates 402 and 404 were employed in the abovecatalytic carbonitrile formation (Schemes 29 and 30, re-spectively).65

The reaction of 2,4,4-trimethyl-1-pentyl ester 402 afford-ed 2-naphthonitrile (382) and 2,4,4-trimethylpentan-1-ol(403) in 81 and 72% yield, respectively (Scheme 29).

Interestingly, the treatment of a-keto azide 404 providedbenzonitrile 386 and the corresponding benzoic acid 405(Scheme 30, part a). The use of isotope oxygen (18O2) re-vealed that one of the oxygen atoms from the molecularoxygen is incorporated into the benzoic acid. The reactionof 404 in the presence of styrene (406) (1 equiv) under thecatalytic conditions gave benzonitrile 386 (76% yield)and benzoic acid 405 (54% yield) along with styrene ox-ide (407) in 9% yield (analyzed by GC) (Scheme 30, partb). This indicated that an (acylperoxy)copper species67

might be involved in the catalytic cycle.

Scheme 29

Scheme 30

Scheme 31

Based on these results, a mechanism for this aerobicCu(OAc)2-catalyzed carbonitrile formation was proposed,as shown in Scheme 31. In this possible mechanism, im-inylcopper intermediate II is formed from the a-azido car-

bonyl compound on elimination of molecular nitrogen viathe deprotonation of I. The oxidation of II with oxygen af-fords peroxycopper(III) species III, which adds to the in-tramolecular carbonyl group to induce carbon–carbonbond cleavage delivering the carbonitrile and (acylper-oxy)copper IV. Protonation of (acylperoxy)copper spe-cies IV provides carboxylic acid V with the regenerationof the Cu(II) salt. When ester substrates are used, furtherdecarboxylation of V proceeds to afford the correspond-ing alcohols.

The stoichiometric reaction under an argon atmosphere(see Scheme 27) indicated that iminylcopper(II) II couldform the carbonitrile and acylcopper VI by b-carbon elim-ination as another mechanistic possibility (Scheme 32,path a). In addition, it could also be speculated that peroxy-copper III undergoes b-fission to lead to the formation ofthe carbonitrile and acylcopper VII, which isomerizes to(acylperoxy)copper IV (path b).

Scheme 32

4.3 Copper(II)-Catalyzed Aerobic Synthesis of Azaspirocyclohexadienones

To further broaden the substrate scope of the above-men-tioned Cu(II)-catalyzed aerobic carbonitrile formation,the reactions of a-azido amides were tested. The morpho-line-derived amide 408 provided the corresponding car-bonitrile product, 2-naphthonitrile (382), in good yield(Scheme 33), although a longer reaction time (36 h) wasrequired compared with that for the synthesis from esters(see Scheme 27).

Scheme 33

N-Phenyl-substituted amide 409 was next subjected to 20mol% of Cu(OAc)2 in the presence of potassium phos-phate at 80 °C under an oxygen atmosphere to confirm theco-product after the expected carbon–carbon bond cleav-age (i.e., N-methylaniline) (Scheme 34).68 In this case, thereaction was complete within 4 hours and, surprisingly,azaspirocyclohexadienone 410 was isolated in 77% yieldwithout any observation of the carbon–carbon bond cleav-

382 81%

HO+

403 72%

Cu(OAc)2 (20 mol%)K2CO3 (1 equiv)


N3

O

O

402

CN

(18O)

405 54%

404

386 76%

MeO

N3

O

OMe Cu(OAc)2 (20 mol%)K2CO3 (1 equiv)

DMF (0.1 M), 60 °C under O2 (18O2) (1 atm)

+

CN

MeO O

OMe

HO

404

+

(a)

(b)

386 81% 405 63%



Ph406

(1 equiv)

+

PhO

407 9%

+

[CuII]

II

N2, H+

R1

N

N2

O

R2

[CuII]

H

R1

N

O

R2

[CuII]

O

R2HOH–R2

CO2

(R2 = alkoxy)

I

V

O

R2O

IV

O[CuII]

H+

O2

III

R1

N

O

R2

[CuIII]O

OC NR1

R1

N

N2

O

R2

II

R1

N

O

R2

[CuII]

O

R2[CuII]

VI

O

R2O

IV

O[CuII]

R1

N

O

R2

[CuIII]OO

III

O2

O

R2[CuIII]O

O

VII

path a

path b

O2

R1–CN

R1–CN


DMF, 60 °Cunder O2 (1 atm)

36 h382 73%

N

O

R

[Cu]

Ar

CNN3

N

O

O

408

Dow

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age. The use of 18O2 revealed that one of the oxygen atomsfrom molecular oxygen is installed in the resulting carbo-nyl group of azaspirodienone 410. The reaction with 1equivalent of Cu(OAc)2 under an argon atmosphere ex-clusively provided a-keto amide 411, which was formedvia hydrolysis of the corresponding iminylcopper speciesor N-H imine.

Scheme 34

The spirodienone structures have commonly been con-structed by the oxidative treatment of phenol deriva-tives.69,70 This unprecedented and mechanisticallyintriguing formation of azaspirodienones, as well as thepotential pharmaceutical properties of their derivatives,71

drove us to explore the substrate scope of our reaction(Table 20).68 By varying substituent R1, aryl rings bearingvarious groups (regardless of their electronic nature)could be introduced, as in the formation of 412–421. Thisprocess could also keep carbon–halogen bonds intact,such as those in the reactions to give 417–420. Alkylgroups as R1, such as those in 422 and 423, were not via-ble for this transformation. Azaspirodienones 424, 425,427, and 428 bearing electron-donating substituents onthe cyclohexadienone ring were formed in good yields. Inaddition to methyl as substituent R2 on the amide nitrogen,phenyl and benzyl groups could be used, such as in thesynthesis of 426 and 428, respectively.

During the course of this study, the reactions of certainsubstrates gave significant mechanistic information. Thereaction of azide 429, sterically hindered by a 2,6-dimeth-ylphenyl group, afforded azaspirodienone 430 in 25%yield along with N-phenylimine 431 in 36% yield(Scheme 35, part a). The latter compound could beformed by the transfer of the phenyl group from the amidenitrogen to the imine nitrogen via an intramolecular ipso-substitution reaction of the corresponding iminylcopper.Interestingly, the treatment of N-4-tolyl amide derivative432 under the catalytic conditions afforded diastereomersof azaspirocyclohexadienol 433 and demethylated aza-spirodienone 410 in 42 and 6% yield, respectively, with-out the formation of expected spirocyclohexa-2,4-dienone434 (Scheme 35, part b).

Based on these results, a mechanistic pathway was pro-posed, as depicted in Scheme 36. In this mechanism, thedenitrogenative formation of iminylcopper II via deproto-

nation of I occurs, which is followed by the oxidation ofII with molecular oxygen to form peroxycopper(III) III.The formation of azaspirocyclohexadienol in the reactionof N-4-tolylamide 432 (Scheme 35, part b) indicates thatthe intramolecular imino-cupration of III might occur toform carbon–nitrogen and carbon–copper bonds concur-rently at the ipso- and para-positions of the benzene ring,

N

OMe

N

Cu(OAc)2 (20 mol%)K3PO4 (1 equiv)

DMF, 80 °C, 4 hunder O2 (18O2)

(1 atm)

NNMe

O

O (18O)

N2

409 410 77%

N

OMe

OCu(OAc)2 (100 mol%)

K3PO4 (1 equiv)

DMF, 80 °C, 4 hunder Ar

409

411 68%

Table 20 Copper(II) Acetate Catalyzed Synthesis of Azaspirocy-clohexadienonesa,b

a The reactions were carried out using 0.5 mmol of the a-azido amide with 20 mol% of Cu(OAc)2 and 1 equiv of K3PO4 in DMF (0.1 M) at 80 °C under an O2 atmosphere.b Isolated yields are shown next to the corresponding products.c 1-Naphthonitrile and N-methylaniline were also obtained in 21 and 19% yield, respectively.d 4-Methoxybenzonitrile and N-methylaniline were also obtained in 27 and 12% yield, respectively.e NaOMe (1 equiv) was used as a base.f N-Methylaniline was obtained in 45% yield.

R1

NNMe

O

O

412: R1 = 3,5-Me2C6H3; 78%413: R1 = 4-PhC6H4; 75%414: R1 = 2-naphthyl; 83%415: R1 = 1-naphthyl; 55%c

416: R1 = 4-MeOC6H4; 65%d

417: R1 = 4-ClC6H4; 81%418: R1 = 4-BrC6H4; 80%419: R1 = 3,5-F2C6H3; 76%420: R1 = 3,5-(F3C)2C6H3; 65%421: R1 = 4-NCC6H4; 69%422: R1 = 1-adamantyl; 29%e

423: R1 = Me; 0%e,f

Ph

NNPh

O

O

Ph

NNMe

O

OMeMe

427: 75%

Ph

NNMe

O

OMeOOMe

Ph

NNMe

O

OMeO

424: 60% 425: 60% 426: 77%

Ph

NN

O

OMeMe

428: 72%

Ph

N

O

NR2

N2

R1

R3 Cu(OAc)2 (20 mol%)K3PO4 (1 equiv)

DMF, 80 °Cunder O2 (1 atm) R1

NN-R2

O

O

R3

Scheme 35

N

OMe

NMe

Me

Cu(OAc)2 (20 mol%)NaOMe (1 equiv)


Ar

NNMe

O

O

Ar

HN

OMe

N+

N2

PhN

OMe

NN2

Me

(Ar = 2,6-dimethylphenyl)

Cu(OAc)2 (20 mol%)K3PO4 (1 equiv)


429 430 25% 431 36%

432

(a)

NNMe

OPh

Me

O

434 0%

(b)

NNMe

OPh

HOMe

NNMe

OPh

MeOH

+

+

433-(5R*,8R*) 433-(5S*,8S*)18% 24%

NNMe

O

O

Ph

410 6%

Dow

nloa

ded

by: U

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rsity

of O

xfor

d. C

opyr

ight

ed m

ater

ial.

42 S. Chiba ACCOUNT


respectively, affording IV. The subsequent isomerizationof IV to give peroxydiene V followed by elimination ofhydroxidocopper(II) species VI72 would form the aza-spirodienone. The observed transfer of the phenyl groupshown in Scheme 35, part a, might proceed via carbon–nitrogen bond cleavage of IV.

5 Conclusion

We have explored the intriguing chemical reactivities ofseveral organic azides, such as vinyl azides, cyclic 2-azidoalcohols, and a-azido carbonyl compounds, which canlead to various kinds of synthetic transformations to givenitrogen-containing molecules. Although there is a gener-al conception that ‘organic azides = 1,3-dipolar cyclo-addition (click chemistry)’, organic azides potentiallypossess diverse chemical reactivities working as a one-nitrogen unit which can be driven by the elimination ofmolecular nitrogen.

Acknowledgment

Our co-workers whose names appear in the references are gratefullyacknowledged for their intellectual and experimental contributions.The work was supported by funding from Nanyang TechnologicalUniversity, Singapore Ministry of Education (Academic ResearchFund Tier 2: MOE2010-T2-1-009), and the Science and Engineer-ing Research Council (A*STAR grant No. 082 101 0019).

References

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Scheme 36

[CuII–OH]

N

O

NR2

[CuII]

R1

N

O

NR2

[CuIII]

R1

OO

NN

R1

O

R2

O H

O [CuII]

base[Cu(OAc)2 for initiation]

N2, H+•base

O2

II

III

IV

V

NN

R1

O

R2

[CuIII] H

O O

VI

N

O

NR2

N2

R1

IH

Ph

[CuII]

base

N

O

NR2

N2

R1

Ph

NN

R1

O

R2

O

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44 S. Chiba ACCOUNT


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application of organic azides for the synthesis of nitrogen...

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