Application of Organic Azides for the Synthesis of Nitrogen-Containing Molecules

ACCOUNT 21

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

Organic azides possess diverse chemical reactivities.4 Abstract: In this account, recent advances made on the reactions of several types of organic azides, such as vinyl azides, cyclic 2-azido Owing to their 1,3-dipole character, they undergo [3+2] alcohols, a-azido carbonyl compounds, towards the synthesis of cycloaddition with unsaturated bonds, such as those in nitrogen-containing molecules are described. alkynes and alkenes as well as carbonitriles (Scheme 1, part a).5 Organic azides can also be regarded as nitrene 1 Introduction equivalents (Scheme 1, part b).6 Accordingly, their reac- 2 Chemistry of Vinyl Azides tions with nucleophilic anions, electrophilic cations, and 2.1 Thermal [3+2]-Annulation of Vinyl Azides with 1,3-Dicar- radicals can formally provide the corresponding nitrogen bonyl Compounds 2.2 Manganese(III)-Catalyzed Formal [3+2]-Annulation with anions, cations, and radicals, respectively, forming a new 1,3-Dicarbonyl Compounds bond with the internal azido nitrogen and releasing molec- 2.3 Manganese(III)-Mediated/Catalyzed Formal [3+3]-Annu- ular nitrogen. Moreover, the generation of anions, cations, lation with Cyclopropanols and radicals at the a-position to the azido moiety can re- 2.4 Synthesis of Isoquinolines from a-Aryl-Substituted Vinyl sult in rapid denitrogenation to deliver the corresponding Azides and Internal Alkynes by Rhodium–Copper Bimetal- iminyl species, which can be used in further synthetic lic Cooperation transformations (i.e., carbon–nitrogen bond formation). 3 Chemistry of Cyclic 2-Azido Alcohols 3.1 Manganese(III)-Catalyzed Ring Expansion of 2-Azido-

cyclobutanols (a) 1,3-Dipoles N

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

alkenes R N N CC

Alcohols N CC R N

triazolines N

4 Chemistry of a-Azido Carbonyl Compounds CC alkynes CC

triazoles

4.1 Orthogonal Synthesis of Isoindole and Isoquinoline Deriv- R N

CN nitriles N R NNN

atives CN 4.2 Generation of Iminylcopper Species and Their Catalytic tetrazoles

Carbon–Carbon Bond Cleavage under an Oxygen Atmo- (b) Nitrene equivalents

sphere N

R N N R

N N 2 4.3 Copper(II)-Catalyzed Aerobic Synthesis of Azaspirocyclo- nitrenes hexadienones

5 Conclusion with carbanions or other nucleophiles

–

+ + R N N N R N X 2 Key words: azides, nitrogen-containing heterocycles, radical reac- N X with carbocations

tions, redox reactions, oxygenations

+ Downloaded by: University of Oxford. Copyrighted material.

+ + R N N N R N C N C 2

with carbon radicals

R N N + R N N C N C 2

1 Introduction chemistry of α-azido anions, cations, and radicals

N N + C N N

The chemistry of organic azides commenced with the syn- C N 2

N N 1 +

C N N thesis of phenyl azide by Griess in 1864 and the discov- C N 2

N N

+ ery of the rearrangement of acyl compounds with C N N C N 2 2 hydrogen azide (HN3) by Curtius in 1890. Since 1950, various synthetic organic reactions have been developed Scheme 1 using acyl, aryl, and alkyl azides, which have been extensively applied for the synthesis of nitrogen-containing We have been interested in the intriguing chemical reac- azaheterocycles as well as peptides.3 tivity of organic azides, such as vinyl azides, cyclic 2-azido alcohols, and a-azido carbonyl compounds (Scheme 2). In this account, we describe recent advances made on the reactions of these organic azides towards the SYNLETT 2012, 23, 21–44 xx.xx.2011 synthesis of nitrogen-containing molecules which have Advanced online publication: 09.12.2011 been developed in our research group. DOI: 10.1055/s-0031-1290108; Art ID: A59911ST © Georg Thieme Verlag Stuttgart · New York

22 S. Chiba ACCOUNT

N inyl species serve for the formation of carbon–nitrogen

N R

N bonds. In this section, we present the synthesis of azahet-

N N HO

R' erocycles from vinyl azides via several types of reaction R N

N mode based on the above chemical reactivities.

-azido carbonyl

cyclic 2-azido a vinyl azides

compounds alcohols

Scheme 2 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- 2 Chemistry of Vinyl Azides azirine derivatives,11 it was found that the reaction of azirine 1 with acetylacetone (2) in 1,2-dichloroethane at room Intermolecular annulation reactions can allow for the temperature gave tetrasubstituted pyrrole 3 in quantitative straightforward and selective construction of complex cy- yield after 33 hours (Scheme 4).

clic molecular structures in a one-pot manner from rela-

EtO C

2 tively simple building blocks, one of the most ideal COMe Cl

7 Cl

O O CO Et processes in organic synthesis from an atom- and step- 2

+ N

8 N

economical point of view. Inspired by this perspective, Me H DCE Cl

Cl r.t., 33 h

(1.2 equiv) 2 we have recently been interested in the application of vi- 1 quant nyl azides as a three-atom unit including one nitrogen for 3 various types of annulation reactions to prepare azahet- Scheme 4 erocycles. One of the attractive chemical properties of vinyl azides is While the reaction of azirine 1 with acetylacetone (2) in their ability to undergo thermal decomposition to give tetrahydrofuran (THF) has been reported, the yield of pyr- highly strained three-membered cyclic imines, 2H-azir- role 3 was low.12 The generation of 3 in high yield in the ines, via vinylnitrene intermediates following denitroge- above reaction (Scheme 4) led us to further investigate the nation (Scheme 3, part a).9 Moreover, the carbon–carbon pyrrole formation. double bond of vinyl azides can be used for the formation The reaction may proceed through the addition of acetyl- of new carbon–carbon bonds with appropriate organome- acetone (2) to the imino carbon of azirine 1,13 followed by tallic compounds (R′–[M]) or radical species (R¢) which nucleophilic attack of the nitrogen in the resulting aziri- results in the generation of iminyl metals or iminyl radi- dine to a carbonyl group with concurrent ring opening of cals, respectively (Scheme 3, parts b and c).10 These im- the strained three-membered ring.14 However, the insta-

bility and poor accessibility of the 2H-azirines prevented

R us using this strategy as a synthetic method for pyrroles. R

N Δ

(a) Accordingly, we planned to use vinyl azides as precursors

– N N N

2 15

H -azirines 2 N of 2H-azirines which can be easily synthesized and han-

vinylnitrenes dled (Scheme 5).

R' As proposed in Scheme 5, simple heating of a mixture of

R'–[M] [M] N

(b)

N ethyl 2-azido-3-(2,6-dichlorophenyl)acrylate (4) and

N N – N

2 [M]

N N acetylacetone (2) in toluene at 100 °C provided pyrrole 5 16

in 86% yield (Table 1, entry 1). Various 2-azido-substi- Downloaded by: University of Oxford. Copyrighted material.

R' tuted cinnamates possessing electron-donating and -with-

R N

N N – N drawing groups on the phenyl group (entries 2–8), as well

2 N

N N as a derivative containing a pyridyl moiety (entry 9), re- Scheme 3 acted with acetylacetone (2) to give the corresponding 2-

Biographical Sketch

Shunsuke Chiba was born University of Tokyo (work- Nanyang Technological in Zushi, Kanagawa, Japan, ing under Professor Koichi University, Singapore, as an in 1978. He obtained his Narasaka). He was appoint- assistant professor. His re- B.Eng. from Waseda Uni- ed as a research associate at search focus is methodology versity in 2001 and received the University of Tokyo in development in the area of his Ph.D. in 2006 from the 2005. In 2007, he moved to synthetic organic chemistry.

Synlett 2012, 23, 21–44 © Thieme Stuttgart · New York ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 23

17,18

2 2

COMe

R indoles via intramolecular C–H amination. It is note-

O Δ

1 worthy that the above intermolecular reactions of 2-azido-

– N

R Me 2 Me Me

2 – H O

H 2 2 substituted cinnamate derivatives with acetylacetone (2)

gave pyrroles exclusively without any indole formation.

– N – H O 2

2 As b-substituents (R1) of azidoacrylates, ethoxycarbonyl

R R COMe

R R

O and alkyl groups could be introduced, giving the corre- N

O H N

H O

R sponding pyrroles in good yields (entries 12 and 13). Sim-

OH N

Me O

Me ple azidoacrylate 30 also reacted smoothly (entry 14). B

A Using a-aryl-substituted vinyl azides, not only phenyl Scheme 5 groups, but also naphthyl, indolyl, pyrrolyl, and ben- zothiophenyl moieties could be installed at the 3-position of the resulting trisubstituted pyrroles (entries 15–26). a- arylpyrroles in good yields. Vinyl azides 22 and 24 bear- Alkyl-substituted vinyl azide 56 reacted smoothly to give ing acetyl and (dimethylamino)carbonyl moieties instead the corresponding pyrrole 57 in 82% yield (entry 27). An of an a-ethoxycarbonyl group could be employed to give E,Z-mixture of 2-phenylvinyl azide (58) could also be the corresponding pyrroles 23 and 25 (entries 10 and 11, used to prepare trisubstituted pyrrole 59 in 85% yield (en- respectively). It is known that the thermolysis of 2-azido- try 28). Tetrasubstituted pyrroles 61 and 63 were success- substituted cinnamates and their derivatives delivers 1H-

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

R R COMe

R O O Δ

– N R Me

2 Me Me

2 – H O H

2 2

Vinyl azides Entry Pyrroles Entry Pyrroles Vinyl azides

86% 5 : R = 2,6-Cl 4 1 2

: R = H 6 93% 7 2

: R = 4-Me 8 90% 9

EtO C COMe

TsN 92% 51

50 Me 24 CO Et N : R = 2-Me 10 89% 11 4

: R = 3-NO 12 R

5 96% 13

3 N

: R = 4-Br 14 90% 15 Me 6

: R = 4-CN 16 90% 17 R 7 H

c : R = 4-MeO 18 81% 19 8

EtO C COMe TsN 2 Me

52 92% 53

25 N

CO Et

94% 20 9 21

N N N

H 3

H N N

R COMe

2 O

d = COMe : R 22 74% 23

96% 55 26

= CONMe : R 24 N 11 quant 25 Me

2 3 N

H Me

3 H

C COMe EtO

12 CO Et 27 82%

26: R = CO Et

2 2

29 96%

= CH Ph 28: R

R Me

1 Ph

= H 30: R

31 85% 14 56 27 57 82%

3 Me

33 75%

R = H 32: Downloaded by: University of Oxford. Copyrighted material. N 15

34: R = 4-Me 35 98% 16

36: R = 4-OMe 37 95% 17

COMe R

COMe

38: R = 2-OMe 39 86% 18

40: R = 4-Br 41 92%

59 85% 3 58 28

42: R = 3-Br Me

43 91%

E Z : = 1:1) (

Me 44: R = 4-CO H 45 86% 21 2

COMe

47 94% 46

60 29 61 66%

N 3 H 3 Me

O Me

COMe Me

49 65% 30 62 48 23 63 91%

N N

3 Me Me

N N

H H 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.

and 62 (entries 29 and 30, respectively). Compoundsa

1,3-Dicarbonyl

b Entry Vinyl azides The scope of the reaction using different 1,3-dicarbonyl Pyrroles

compounds was next investigated with several vinyl compounds

azides (Table 2).16 The reactions of 1,3-diketones bearing O EtO C O O

CO Et

terminal alkene moieties or phenyl groups, such as 64 or 2 1

N 3

68, respectively, with several vinyl azides resulted in the Me

H Me

90% 64

formation of the corresponding pyrroles (entries 1–4). The 65

reactions of b-keto aldehyde 70 proceeded smoothly with O

EtO C

CO Et

C vinyl azides 6 and 26 forming tri- and tetrasubstituted pyr- EtO 2 64 2

N EtO C

3 2

roles 70/71 and 73/74 in almost 1:1 ratios (entries 5 and 6, N

26 H 94%

respectively), probably via nucleophilic attack of the ni- 66 trogen atom to both carbonyl groups (see Scheme 5, A to O

B). However, the treatment of vinyl azides 6 and 58 with 64 3

N a b-keto ester, ethyl acetoacetate (75), resulted in sluggish 3

H 80%

reactions, giving the desired pyrroles 76 and 77 in only 30 67

O and 58% yield (entries 7 and 8, respectively) along with O

complex mixtures.

4 32

95%

2.2 Manganese(III)-Catalyzed Formal [3+2]- 69

Annulation with 1,3-Dicarbonyl Compounds O

EtO C 2

Besides the above-mentioned thermal [3+2]-annulation of

O O

Et vinyl azides and 1,3-dicarbonyl compounds, we planned CO 54% 71 2

H +

EtO C to use the carbon–carbon double bond of vinyl azides for CHO N 2

the formation of a new carbon–carbon bond to initiate an- 3 6

other type of annulation reaction. N H

43%

Our reaction design was based on the addition of a carbon 72

radical bearing a carbonyl group to the carbon–carbon O EtO C

double bond of a vinyl azide to provide a new carbon–car- 2

EtO C

bon bond with the generation of an iminyl radical. The im- N

CO Et

2 H

41% 73

EtO C

inyl radical would then intramolecularly form a carbon– 70 + 6 N EtO C CHO 3

nitrogen bond with the carbonyl, resulting in cyclization 2 26

19,20 EtO

leading to various azaheterocycles (Scheme 6). The N

39%

proposed process could potentially be achieved in a redox 74

catalytic manner featuring two key redox steps: (1) oxida- O

EtO C

OEt

CO Et

2 O

tive generation of the radical species by the reaction of O

n 7 N

OEt Me 3

radical sources with a metal oxidant [M ] (to become N

75 H

30%

[Mn–1]) (oxidative initiation) and (2) reduction of the re- 76 n–1 O sulting iminyl radical by [M ] and its cyclization with Downloaded by: University of Oxford. Copyrighted material.

the intramolecular carbonyl group to give azaheterocycles OEt

n 3

and regenerate [M ] (reductive termination). N

58 H

77 58%

radical C

sources a N

[M ] C The reactions were carried out by heating a mixture of the vinyl

oxidative initiation

azaheterocycles azide (0.3–0.5 mmol) and 1,3-dicarbonyl compound (1.2 equiv) in

n-1

[M ]

R toluene at 100 °C for 2–24 h. R

C b

C Isolated yields are shown. N

C N

] O[M N C

O N Based on this concept, manganese(III) acetate, which has

been extensively used for oxidative radical reactions us-

R 21

C ing carbonyl compounds, was employed in the reaction

2 N

R of 1-phenylvinyl azide (32) and ethyl acetoacetate (75) in

[M ] C

N methanol (MeOH) under a nitrogen atmosphere. As ex-

reductive termination

n-1

O ] [M pected, the reaction proceeded smoothly at 40 °C using 10 mol% of manganese(III) acetate in the presence of acetic Scheme 6 acid (AcOH), affording trisubstituted pyrrole 77 in 94% yield (Scheme 7). This catalytic reaction is initiated by the

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

ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 25

CO Et

Mn(OAc) O (10 mol%) addition of manganese(III) enolate I to vinyl azide 32 in ⋅2H 3 2

O O

the radical pathway, giving iminyl radical II with the re- AcOH (2 equiv)

Me OEt N

MeOH, 40 °C, 2 h

N lease of a manganese(II) [Mn(II)] species and molecular H (1.5 equiv)

94% nitrogen. The reaction of iminyl radical II with the Mn(II) 77 75

species affords iminylmanganese(III) [(alkylideneam- 32

ino)manganese(III)] III, the nucleophilic attack of which EtO

O O

III Ph

] to a carbonyl group yields cycloaddition intermediate IV. [Mn

Me OEt [Mn ], N

Finally, protonation of IV with AcOH followed by dehy- N 75 Me

dration yields pyrrole 77 along with regeneration of N

AcOH N 32

Mn(III). EtO

The scope of this catalytic pyrrole formation was found to III

Mn (OAc)

3 Ph O

be quite broad. A series of vinyl azides could be employed N

19b EtO

with ethyl acetoacetate (75), as shown in Table 3. a- AcOH

CO Et 2

] Aryl-substituted vinyl azides reacted smoothly to afford [Mn

O Me

N the corresponding pyrroles in good yields (entries 1–9). O

CO Et

III

[Mn ]

III

[Mn ] Tetrasubstituted pyrrole 87 could be synthesized from 2- Me

N III

methyl-1-phenylvinyl azide (62) in good yield (entry 9). OH

H O

The reaction of 2-pyrrolylvinyl azide 52 gave bipyrrole 88 2 in 68% yield (entry 10). 1,4-Dipyrroylbenzene 90 could 77 be obtained by treatment of 1,4-bis(1-azidovinyl)benzene Scheme 7

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

2 1

R CO Et R

O O

2H O cat. Mn(OAc) ⋅ 3 2

R 1

R Me OEt Me

MeOH, 40 °C N

H 2 75

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

CO Et

CO Et 2 2

13 20 2

R Me

O N

N 3

N (85) 93 92 3 (94) 77 1 2 10 : R = H 32

2 : R = 2-Br 78 10 2 (94) 79

CO Et 2

(86) 80 : R = 4-Br 40 3 10 2

Me : R = 4-CO 44 2 4 10 (88) 81

N : R = 3-NO 82 2 5 10 (95) 83

H N

3 10 (78) 84 : R = 4-Me 6 34 4

(75) 85 : R = 2-OMe 38 10 7 4 (94) 95 14 : R = Ac 20 1 94

: R = Si( t -Bu)Ph 96

20 2 (85) 15 97 CO Et 2 2

CO Et 8202

16 40 1 H

N Me

N 86 (83)

Me CO Et 2

98 (60)

60 Downloaded by: University of Oxford. Copyrighted material. Me

20 2 9

CO Et Me

OAc

N O

3 t- Bu H

OAc

87 (72)

40 Me 5

t- Bu

N O

CO Et O

2 Si

N t- Bu

3 t- Bu

10 20 24

N N 99

100 (74) Me

Ts H

CO Et

c 52 2

88 (68)

EtO C

2 N

EtO C Me

N 18

EtO C Me

N N

3 40 24

30 Me CO Et

H 101 (98)

90 (48) N 89

EtO C

CO Et

19 20 24

12 20 3

EtO C Me

91 (90)

e 56

102 (78) N 3 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.

(89) with 40 mol% of manganese(III) acetate, although afforded pyrrole 114 in 76% yield after 20 hours the yield was moderate (entry 11). a-Alkyl-substituted vi- (Table 5).19b Treatment of other vinyl azides with acetyl- nyl azides could also be used for this pyrrole formation, acetone (2) using 20 mol% of Mn(pic)3 led to the forma- giving the corresponding pyrroles in good yields (entries tion of pyrroles 115–118 in moderate to good yields, 12–17). Bicyclic pyrrole 98 was obtained in 60% yield whereas electron-deficient vinyl azide 30 delivered the from 1-azidocyclooctene (60) (entry 16). Vinyl azide 99 desired pyrrole 119 in only 28% yield along with a com- bearing a chiral polyol functionality22 could be converted plex mixture. The reaction of 1,3-diphenylpropane-1,3- into pyrrole 100 in 74% yield (entry 17). Azidoacrylates dione (112) with vinyl azide 32 gave a moderate yield of could also be employed in the above catalytic process (en- pyrrole 120, probably owing to the steric hindrance of the tries 18 and 19). While the reaction of ethyl 2-azidoacry- benzoyl group. The reaction of unsymmetrical 1,3-dike- late (30) needed only 5 mol% of manganese(III) acetate to tone benzoylacetone (113) with vinyl azides proceeded to complete within 2 hours, affording pyrrole 101 almost afford pyrroles 121–123 in moderate to good yields as the quantitatively (entry 18), that of 2-phenylvinyl azide 6 re- sole products via carbon–nitrogen bond formation with quired a longer reaction time (24 h), probably owing to the less-hindered acetyl group. steric hindrance (entry 19). Table 5 Reactions of Vinyl Azides with 1,3-Diketones Catalyzed Next, the generality of this reaction using different b-keto by Manganese(III) Tris(pyridine-2-carboxylate)a,b esters was examined with 1-phenylvinyl azide (32) and

ethyl 2-azidoacrylate (30), as shown in Table 4.19b By N

varying the substituent on the b-keto ester through the use O

(20 mol%) O

2 3

2 of 103–105, phenyl, ethoxymethyl, and cyclopropyl 1

R R O O AcOH (2 equiv)

groups could be successfully installed at the C-2 position +

1 4

R R R

MeOH, 40 °C N

of the resulting pyrrole to give products 106–111. H

(1.5 equiv)

N 2

Table 4 Manganese Acetate Catalyzed Synthesis of Pyrroles from 1,3-diketones O O O O

Vinyl Azides and 1,3-Dicarbonyl Compoundsa,b O

Me Me

CO Et 112 2 113 2

Me COMe COMe COMe

cat. Mn(OAc) •2H O

3 2 AcO

AcOH (2 equiv)

O O

32 R Me

N or N

H H

OEt R

CO Et MeOH, 40 C

° 2

EtO C

: R = H; 76% ( + ) 114 32 2 : 41% ( + ) 117 62 2 (1.5 equiv) : 71% ( + ) 118 94 2

: R = 3-NO ; 80% ( + ) 115 82 2

EtO C R

: R = 4-Me; 52% ( + ) 116 34 2

N H 2

COMe

β-keto esters:

O O

O O O O EtO C

2 N

OEt

R EtO H

OEt

: R = H; 61% ( + ) 121 32 113

103 104 105 : 28% ( + ) 119 30 2 : 32% ( + ) 120 32 112

: R = 4-Br; 55% ( + ) 122 40 113

CO Et CO Et CO Et

2 2 2 Me; 85% (44+113) 123: R = 4-CO 2

OEt

N N

N a

H H H Reactions were performed with 0.3 mmol of the vinyl azide under a

: 63% (32+103) 108: 55% (32+104) 110: 56% (32+105) 106 N2 atmosphere.

Downloaded by: University of Oxford. Copyrighted material.

Et CO Et CO Et CO Isolated yields are shown next to the corresponding products. 2 2

2 c Vinyl azide 32 was recovered in 27% yield.

OEt

EtO C EtO C EtO C

2 2 2 N N N

H H H

111: 72% (30+105) : 72% (30+103) 109: 77% (30+104) 107 b-Keto acids have been used as either a-carbonyl anion24 or radical25 equivalents with the elimination of carbon di- a Reactions were performed in MeOH at 40 °C with 1.5 equiv of the oxide. Our findings on the reactivity of vinyl azides to- 1,3-dicarbonyl compound under a N2 atmosphere. wards the a-carbonyl radicals derived from b-keto esters b Isolated yields are shown next to the corresponding products. and 1,3-diketones with Mn(III) catalysts drove us to ex- amine the reaction of vinyl azides and b-keto acids. In this The reaction of acetylacetone (2) instead of b-keto esters case, Mn(acac)3 suitably catalyzed the reaction to synthe- with vinyl azide 32 in the presence of 20 mol% of manga- size the corresponding substituted pyrroles. nese(III) acetate was sluggish, and pyrrole 114 was ob- The reactions of various vinyl azides with b-keto acid 124 tained in low yield (21%) along with the recovery of vinyl are summarized in Table 6.19a The reaction of a-aryl-sub- azide 32 (63%), even after 24 hours. To improve the prod- stituted vinyl azides with 124 provided the desired bicy- uct yield in the reaction with acetylacetone (2), other clic pyrroles in good yields (entries 1–6). Notably, the Mn(III) complexes were screened. Although manga- reaction of vinyl azide 50 bearing an a-indol-2-yl substit- nese(III) acetylacetonate [Mn(acac)3] displayed no cata- uent resulted in the formation of 2,2¢-biindole derivative lytic activity in this reaction, the use of 20 mol% of 23 130 (entry 6). 2-Azidoacrylate derivatives 30 and 26 manganese(III) tris(pyridine-2-carboxylate) [Mn(pic)3]

Synlett 2012, 23, 21–44 © Thieme Stuttgart · New York ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 27

could also be used, giving the corresponding bicyclic pyr- Table 7 Scope of the Reaction Using Different b-Keto Acidsa

O roles 131 and 132 in good yields (entries 7 and 8, respec- O

tively). In the case of vinyl azide 26, the presence of an 1 cat. Mn(acac) R OH 3

ethoxycarbonyl group at the b-position did not retard the R

N DMF, r.t.

(1.5–3 equiv)

process, which gave tetrasubstituted pyrrole 132 in 74% H N 32

yield (entry 8). 2

Entry Pyrroles -Keto acids β Yield/%

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

Vinyl Azidesa O

1 133 OH : 70 134

O O

1 2 R

R R

cat. Mn(acac)

3 O O OH

N R

DMF, r.t.

OH N

135

124

: 65 136

N N

(1.5–3 equiv) H

b O Pyrroles Entry Vinyl azides Yield/%

c 3 : n = 1 : 81 137 138

: 83 125 : R = H 32 1

e N

d 4

n : 82 : n = 2 140 139 R

: 92 126

: R = 4-Br 40 2

: 68 127

: R = 4-CO 44 Me

N R

: 91 128 3 N : R = 2-MeO 38

4 O O

H d

: 87 129 : R = 4-MeO 36

5 5 : R = Et 141

: 84 142

OH R

6 : 82 144 : R = Ph 143

H Me

: 78 130

6 50

O O

7 145 : 23 146 N N

Ts H N

OH H

EtO C

c 2

: 68 131

30 7

EtO C

2 a

N Reactions were performed in DMF at r.t. with 1.5–3.0 equiv of the 3 H

b-keto acid under a N2 atmosphere.

EtO C

EtO b

c 2

: 74 132

Et CO Isolated yields are shown.

26 2

8 c

3 30 mol% of Mn(acac) was used.

EtO 3 2

N d H 40 mol% of Mn(acac)3 was used and b-keto acid 135 was added via a syringe pump over 1 h. e a Reactions were performed in DMF at r.t. with 1.5–3.0 equiv of b- 20 mol% of Mn(acac)3 was used. f Mn(pic) (1 equiv) was used; the use of Mn(acac) (1 equiv) afforded keto acid 124 under a N2 atmosphere. 3 3 b Isolated yields are shown. pyrrole 146 in only 10% yield. c 10 mol% of Mn(acac)3 was used. d 20 mol% of Mn(acac)3 was used. nylpyridine (148) was investigated. The possible reaction pathway is depicted in Scheme 8. The reaction is initiated The scope of the b-keto acids in the reaction was next in- by the addition of b-carbonyl radical I, generated via the 32 19a one-electron oxidation of cyclopropanol 147 using the vestigated with vinyl azide (Table 7). Tetrahydro- n pyrano[4,3-b]pyrrole 134 and 4,5-dihydro-1H- metal oxidant [M ], to vinyl azide 32, affording iminyl g 136 radical II with the elimination of molecular nitrogen. The benzo[ ]indole were constructed in good yields by n–1 employing b-keto acids 133 and 135 (entries 1 and 2, re- reaction of iminyl radical II with [M ] affords iminyl- spectively). Bicyclic pyrroles 138 and 140 bearing larger metal species III, and its intramolecular nucleophilic attack to the carbonyl group gives cyclized intermediate IV. carbocycles could also be synthesized in good yields (en- Downloaded by: University of Oxford. Copyrighted material. tries 3 and 4, respectively). In addition, linear b-keto acids Subsequent protonation affords tetrahydropyridine V 141 and 143 could be employed, affording the trisubstitut-

ed pyrroles 142 and 144 in good yields (entries 5 and 6,

HO Ph

respectively). However, b-keto acid 145, the precursor of – H 2

N Ph

Ph N OH Ph

147 [M ] a primary a-carbonyl radical, was not a viable substrate, V

giving only low yields of the desired pyrrole 146 even VI

[O]

n-1 +

[M ], H

when using stoichiometric amounts of different Mn(III) H

O Ph

N complexes (entry 7). Ph

n O [M ]

Ph Ph N

2.3 Manganese(III)-Mediated/Catalyzed Formal 148

[3+3]-Annulation with Cyclopropanols O

O Ph

N Ph

We next focused on the use of cyclopropanols as precur- Ph

[M ] I

sors of b-carbonyl radicals and investigated their addition N III

reactions with vinyl azides followed by carbon–nitrogen N

n-1

]

26 [M

Ph N N bond formation (formal [3+3]-annulation). 2

The reaction of 1-phenylvinyl azide (32) and 1-phenylcy- II clopropanol (147) to give the target compound 2,6-diphe- Scheme 8

n along with regeneration of [M ]. Dehydration of V and terestingly, the corresponding reactions with Mn(pic)3 in subsequent oxidation result in the desired pyridine 148. acetonitrile provided 2,3,6-trisubstituted pyridines 159– We commenced our study on the pyridine formation using 161 in moderate yields. This was probably due to the low a stoichiometric amount of a Mn(III) complex for the ox- solubility of Mn(pic)3 in acetonitrile that would allow idation of cyclopropanol 14727 as well as dihydropyridine only a low concentration of the generated b-carbonyl rad- VI (Scheme 8). It was found that the treatment of a mix- ical so as to prevent its side reactions. ture of vinyl azide 32 and cyclopropanol 147 (1.5 equiv) Next, the catalytic pyridine formation (using conditions with 1.7 equivalents of Mn(acac)3 in MeOH led to the rap- B) was examined for the synthesis of pyridines 148, 150, id consumption of vinyl azide 32 within 5 minutes at room 155, and 157. The yields of the corresponding pyridines temperature. Stirring for a further 1 hour after the addition are shown in parenthesis in Table 8 and are almost compa- of AcOH (2 equiv) afforded 2,6-diphenylpyridine (148) in rable with those obtained under the stoichiometric condi- 84% yield (Scheme 9, part a). It was noted that other met- tions. al oxidants, such as silver(I),28 iron(III),29 or copper(II)30 complexes, were not viable for this transformation. Table 8 Manganese(III)-Mediated Pyridine Formation from Vinyl Azides and Cyclopropanol 147a,b

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

Mn(acac)

with another stoichiometric oxidant for the aromatization (1.7 equiv), r.t., 5 min 3 2

2 then AcOH (2.0 equiv), r.t. / MeOH

1 R R

of dihydropyridine VI to give 148 (Scheme 8). It was re- HO

R N : conditions B

vealed that the treatment of a mixture of vinyl azide 32 N +

Mn(acac) (10 mol%), r.t., 5 min 147 3

147 2 then HCl (2.0 equiv) under O C / MeOH and cyclopropanol with a catalytic amount of , 40 (1.5 equiv) ° 2

Mn(acac)3 (10 mol%) in MeOH also led to the consump-

84% (80%) R = H tion of vinyl azide 32 within 5 minutes at room tempera- 148:

: R = 4-Me 149

ture. The subsequent addition of oxygen (under O , 1 atm) 84% : R = 2-OMe 150

2 71% (70%)

: R = 4-OMe 151

70%

and hydrogen chloride (HCl) (2 equiv) provided the de- N

c : R = 2-Br 152 47%

: R = 4-Br 153 sired pyridine 148 in 80% yield (Scheme 9, part b). 70%

75% (72%) 155

: R = 4-CO 154 Me 70% 2

Mn(acac) AcOH 3

(1.7 equiv) (2 equiv)

(a) N EtO C N N + 2

MeOH, r.t., 5 min

under N

84% 148 2 147

: R 158 = H 51%

(1.5 equiv) 70% 156 66% (50%) 157

: R 159 = Ph 30%

HCl Mn(acac) 3

N N (2 equiv) (10 mol%)

147

(b) 32 80% 148

(1.5 equiv)

under O MeOH, r.t., 5 min

e e 2 45% 52% 160 161

under N 2

Scheme 9 Optimized reaction conditions for pyridine formation a Unless otherwise noted, the reactions were carried out under either using a vinyl azide and a cyclopropanol 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- Using Mn(acac)3 in both a stoichiometric and aerobic cat- dition of AcOH (2 equiv); B: treatment of a mixture of the vinyl azide alytic manner, the generality of this Mn(III)-mediated/cat- (0.3 mmol) and cyclopropanol 147 (1.5 equiv) with Mn(acac)3 (0.1 Downloaded by: University of Oxford. Copyrighted material. alyzed pyridine formation was investigated with various equiv) in MeOH at r.t. under a N2 atmosphere for 5 min, followed by vinyl azides (Table 8).26 the addition of HCl in MeOH (3 M, 2 equiv) with an O2 balloon (1 atm). b By applying the stoichiometric use of Mn(acac)3 (condi- Isolated yields are shown next to the corresponding products. The tions A), the reactions of a range of a-aryl-substituted vi- yields obtained under conditions B are shown in parenthesis. nyl azides with cyclopropanol 147 afforded 2,6- c Vinyl azide 78 was recovered in 30% yield. d diarylpyridines in moderate to good yields. Heteroaryl 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. motifs, such as pyrrolyl and indolyl groups, were success- e The reactions were run using Mn(pic)3 (1.7 equiv) and AcOH (2 fully incorporated into the product, as shown in the forma- equiv) in MeCN at 40 °C at r.t. tion of 156 and 157. The reaction of electron-deficient azidoacrylate 30 provided pyridine 158 in 51% yield. When the reactions of a,b-disubstituted vinyl azides 6, 62, The scope of the cyclopropanols in the reaction was then and 60 were performed using Mn(acac) in MeOH, the investigated with 1-phenylvinyl azide (32) under both the 3 stoichiometric and catalytic reaction conditions (condi- generated b-carbonyl radical underwent self-coupling or 26 hydrogen abstraction preferentially, leading to the desired tions A and B, respectively), as shown in Table 9. 1- pyridines in only trace amounts. This indicated that the Arylcyclopropanols were converted into the correspond- addition of the b-carbonyl radical to the a,b-disubstituted ing 2,6-diarylpyridines in good yields (entries 1–3). vinyl azides was extremely slow owing to the steric hin- Moreover, some alkyl groups (entries 4–7) including drance of the b-substituents on the latter compounds. In- strained cycloalkyls, as in substrates 170 and 172, and a piperidine moiety, as in compound 174, could be installed

Synlett 2012, 23, 21–44 © Thieme Stuttgart · New York ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 29 at C-2 of the pyridine ring. The introduction of alkenyl Table 9 Manganese(III)-Mediated Pyridine Formation from Vinyl

and alkynyl groups on the pyridine ring was a particular Azide 32 and Cyclopropanolsa

feature of this method (entries 8 and 9, respectively). The R conditions A:

Mn(acac) (1.7 equiv), r.t., 5 min method also allowed for the installation of an alkoxycar- 3

then AcOH (2.0 equiv), r.t. / MeOH

R HO

bonyl group as well as a dimethyl(phenyl)silyl moiety 2 N R +

: conditions B

(entries 10 and 11, respectively). The reactions of vinyl 2

Mn(acac) (10 mol%), r.t., 5 min

N 32

(1.5 equiv)

then HCl (2.0 equiv) under O C / MeOH , 40 ° azide 32 and 1,2-disubstituted cyclopropanols 184 and 2

186 with Mn(pic)3 afforded 2,4,6-trisubstituted pyridines

b Yield/%

Entry Cyclopropanols 185 and 187 (entries 12 and 13, respectively). In these Pyridines

cases, secondary b-carbonyl radicals were found to be Condition A Condition B

formed predominantly via the oxidative ring opening of R

HO N 184 and 186, judging from the substitution patterns of the R

products.

: R = 2-Br 70 162 163 1

: R = 4-Br 164 81 2 82 165

: R = 4-Ph

The catalytic reaction (conditions B) provided almost 166 3 167 comparable results for most of the substrates, except in the 66

reactions to give pyridines 175 (entry 7) and 179 (entry 9).

N 4 80 70

We planned to broaden the reaction scope of this Mn(III)- HO 169

mediated pyridine synthesis using other types of cyclo- 168

propanols. The one-electron oxidation of 1-alkoxycyclo- 5 70 73 N

propanols should generate b-alkoxycarbonyl radicals, 170

which we also expected to add to vinyl azides. The reac- 171

tion of vinyl azide 32 and 1-(ethyloxy)cyclopropanol 78 70

N 6

(188) proceeded smoothly and rapidly (within 5 min) us- 172 173

ing 10 mol% of Mn(acac)3 in ethanol (EtOH) at room tem-

82 45

7 N perature to result in the formation of d-keto ester 189 in HO N

very high yield (Scheme 10). In this case, the generated Bn 174

iminyl radical A was reduced by the resulting Mn(II) spe- 175

cies to afford iminylmanganese(III) B, which could not

51 54 8 HO

undergo intramolecular cyclization with the ethoxycarbo- N

177 nyl group, but was protonated to give imine C with regen- 176

eration of the Mn(III) species. Hydrolysis of imine C

9 55 during the workup process delivered d-keto ester 189. 21

178 179

Mn(acac) (10 mol%)

HO OEt

OEt

HO R

3 +

N R

EtOH, r.t., 5 min

O O

under N 188

10 = CO Me 180: R

181

33 N

32 2 (1.2 equiv)

189 96%

11 183

45 = SiMe Ph 182: R 2

R • A proposed reaction mechanism

HO OEt

O OEt Mn(III) HO

Downloaded by: University of Oxford. Copyrighted material.

– Mn(II), H

188 R

184: R = Me 12 185 63

4 Ph O

c 187

40 = Ph 186: R 13

Mn(II)

OEt

N OEt

N a

O Unless otherwise noted, the reactions were carried out under either

A conditions A or B; A: treatment of a mixture of vinyl azide 32 (0.3 32

mmol) and the cyclopropanol (1.5 equiv) with Mn(acac)3 (1.7 equiv)

OEt

H O

2 in MeOH at r.t. under a N2 atmosphere for 5 min, followed by the ad-

189

NH O

N O dition of AcOH (2 equiv); B: treatment of a mixture of vinyl azide 32

– Mn(III) (workup)

[Mn(III)] (0.3 mmol) and the cyclopropanol (1.5 equiv) with Mn(acac) (0.1 C 3 B 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). Scheme 10 b Isolated yields. c The reaction was run using Mn(pic)3 (1.7 equiv) in MeCN at r.t. To keep the nitrogen atom of the putative imine C in the final product, we tried to reduce imine C to give an amine, equiv) was added to the reaction mixture, which provided which would then undergo lactamization to provide a d- d-lactam 190 in 85% yield as expected (Scheme 11). A se- lactam.31,32 After the consumption of vinyl azide 32 in the ries of a-aryl-substituted vinyl azides possessing both reaction with cyclopropanol 188, sodium borohydride (2 electron-withdrawing and electron-donating groups were

With the Mn(III)-catalyzed method to construct a 2-aza-

Mn(acac) (10 mol%)

3 R HO OEt

OEt bicyclo[3.3.1]non-2-en-1-ol structure in hand, the sub- +

EtOH, r.t., 5 min

H N O

N strate scope of the reaction was next investigated

under N 188 2

N 26 (1.2 equiv)

2 (Table 10). A variety of 3-aryl-2-azabicyclo[3.3.1]non-

: R = H; 85%

190 2-en-1-ols were prepared in good to excellent yields; pyr- NaBH

: R = 4-Br; 80% 191

(2 equiv) rolyl and indolyl moieties were successfully incorporated

: R = 4-CO Me; 69% 192

N O

: R = 4-Me; 81% 193

R H into the corresponding products (entries 8 and 9, respec- : R = 4-OMe; 87%

194 tively). The steric hindrance in a,b-disubstituted vinyl Scheme 11 azide 62 made its reaction sluggish, giving the desired compound 205 in only 28% yield along with the recovery of 62 (68%), even in the presence of 40 mol% of the cat- transformed into aryl-substituted d-lactams 191–194 in alyst (entry 10). The introduction of substituents, such as 26a good yields. alkyl, vinyl, and phenyl groups, at C-4 of the bicyclic cy- Next, we envisaged using bicyclic cyclopropanols, such clopropanol did not retard the reaction and provided the as bicyclo[3.1.0]hexan-1-ol (195), as sources of b-carbo- corresponding 2-azabicyclo[3.3.1]non-2-en-1-ols in high nyl radicals. Interestingly, the unusual product 2-azabicy- yields and with good diastereoselectivity (exo-selective, clo[3.3.1]non-2-en-1-ol 196 was isolated in 89% yield on 83:17 to 94:6) (entries 11–15). In these cases, the addition the reaction of compound 195 with vinyl azide 32 using of the b-carbonyl radicals to vinyl azide 32 in the carbon– only a catalytic amount of Mn(acac)3 (5 mol%); the slow carbon bond formation occurred in an anti-selective man- addition of 195 via a syringe pump to a mixture of vinyl ner with respect to the adjacent C-4 substituents to mini- azide 32 and the catalyst over 1 hour was required to com- mize 1,2-steric repulsion. 26 plete the reaction (Scheme 12). It is noteworthy that the Having prepared the 2-azabicyclo[3.3.1]non-2-en-1-ols, treatment of optically active cyclopropanol 195 (85% we then explored their transformation into 2-azabicy- 33 ee) with vinyl azide 32 afforded racemic compound 196. clo[3.3.1]nonane (morphan)27 or 2-azabicyclo[3.3.1]non- The lack of transmission of the chirality of cyclopropanol 2-ene frameworks, which are prevalent in several natural 195 to bicyclic product 196 suggests that the generation of alkaloids as well as biologically active molecules.35 achiral ring-expanded b-carbonyl radical I34 from 195 followed by its radical addition to vinyl azide 32 is involved The treatment of 196 with sodium cyanoborohydride in the reaction mechanism. The radical addition would (NaBH3CN) in the presence of HCl induced the double form iminylmanganese(III) II-eq and II-ax bearing an im- hydride reduction of the carbon–nitrogen double bond and inyl tether in an equatorial- and axial-like position, re- carbon–oxygen bond, affording 2-azabicyclo- [3.3.1]nonane 216 stereoselectively in 70% yield spectively. The conformational inversion of II-eq to II-ax 26a would be indispensable for achieving the further intramo- (Scheme 13). The first hydride attacked the carbon– lecular cyclization of iminylmanganese II-ax with the nitrogen double bond entirely from the less-hindered exo- carbonyl group to give alkoxymanganese(III) species III, face to form hemiaminal I. Subsequent dehydration of I which would protonate to afford 196. gave the bridgehead iminium species II, which could be

reduced by one more hydride to afford product 216.

OH OH

Mn(acac) (5 mol%)

H H 3

NaBH CN (3.0 equiv) 3

N HCl in MeOH (3 equiv) Ph

N N MeOH, r.t., 1 h

195 195 (slow addition of

H 2

MeOH, r.t., 2 h Downloaded by: University of Oxford. Copyrighted material.

(85% ee) through a syringe pump) 196 89%

196

216 70% (1.2 equiv) 32 (0% ee)

• A proposed catalytic cycle • A proposed reaction pathway

196 OH

195 OH

–

III

+ H

H [Mn ] H

Ph N 196

III

O[Mn ]

II + H

O [Mn ], H

N I

– Ph

OH H

III

[Mn(III)]

216

Ph N

–H O H

H O Ph

II-eq O

O Scheme 13

[Mn ] [Mn(III)]

N N

N II-ax

Ph A one-pot conversion could be achieved starting from vi-

32 N

N 2 nyl azide 32 and cyclopropanol 195 using Mn(acac)3 as a catalyst followed by treatment with NaBH CN (3 equiv) Scheme 12 3 and HCl (3 equiv). Product 216 was formed in good yield without the isolation of 2-azabicyclo[3.3.1]non-2-en-1-ol

Synlett 2012, 23, 21–44 © Thieme Stuttgart · New York ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 31

Table 10 Manganese(III)-Catalyzed Synthesis of 2-Azabicy- Table 11 One-Pot Synthesis of 2-Azabicyclo[3.3.1]nonanesa,b

clo[3.3.1]non-2-en-1-olsa

NaBH CN 3

(3 equiv)

Vinyl azides Cyclopropanols Products Yield/% HCl in MeOH Entry

H Mn(acac) H

H (3 equiv) (10 mol%)

2 R

+ R

MeOH, r.t. R

N OH H R

(1.2 equiv) N 2

H N

H H N H

89 195

R = H 32: 196

1 N

2 N

: R = 4-Me 34 95

195 197 2

H H

: R = 2-OMe 38 88 3 195 198

: R = 4-OMe 36

2 c

93 195

199

= CH(CH ) 70% R 220: (85:15) (32+206) 70% ( + ) 32 195

R = H 216:

3 2

: R = 2-Br 78

2 c 5

1 195

70 200

R 221: = CH=CH 67% (81:19) (32+208)

= 4-Me 68% ( + ) R 34 195 217: 2

: R = 4-Br

6 195

201

2 c 83

R 222: = CH CH=CH 80% (81:19) (32+210)

R = 4-OMe 58% ( + ) 218: 36 195

2 2

Me : R = 4-CO 44

195

202 2 7 75

2 c

1 76% ( + ) 40 195 R 223: = Ph 56% (90:10) (32+212) R = 4-Br 219:

TsN

N a

83 203 The reactions were carried out by the addition of a solution of the 195 8 52

H cyclopropanol (1.2 equiv) in MeOH, via a syringe pump over 1 h, to

N Ts

2 a solution of the vinyl azide (0.3 mmol) and Mn(acac)3 (10 mol%) under a N2 atmosphere at r.t.; this was followed by treatment with

OH NaBH CN (3 equiv) and HCl in MeOH (3 M, 3 equiv) for 3 h.

c 3 N

204 77 d

9 b 195 TsN

50 Isolated yields are shown next to the corresponding products.

H c The ratio of the exo- and endo-isomers was determined by 1H NMR Ts N

N spectroscopy, and the major exo-isomer is shown. 2

Me N

d reduction of acetate 224 with triethylsilane induced selec-

d,e

10 195 28 62 205

H tive carbon–oxygen bond cleavage, affording 2-azabicy-

f,g

xo/endo = 8 e 5:15) ( H

N 2 clo[3.3.1]non-2-ene 225 in 90% yield, keeping the

carbon–nitrogen double bond intact. Similarly, treatment OH

OH with trimethylaluminum or allyltrimethylsilane–TiCl

N 4

R 36

N provided a new quaternary carbon center at the bridge-

H R

2 head position, giving products 226 and 227, respectively.

11 32 : R = i -Pr 206 : 90 207 exo/endo = 85:15)

( These transformations might proceed via a bridgehead

f,g

: R = CH=CH 208 32 : 82 209 (exo/endo = 83:17) 12

2 37

f,h

: R = CH 210 CH=CH carbocation, which is then immediately trapped by the : 86 211 (exo/endo = 86:14) 32 13 2 2

: R = Ph 212

f,g

: 91 213 (exo/endo = 94:6) 14

32 corresponding nucleophile.

: R = CH OMOM 214

2 15 : 74 215 (exo/endo = 85:15) 32

a H

Unless otherwise noted, the reactions were carried out by the addi- N

a. Ac O b. TiCl N 4

tion of a solution of the cyclopropanol (1.2 equiv) in MeOH, via a sy- 2 Et SiH 86%

3 H

H ringe pump over 1 h, to a solution of the vinyl azide (0.3 mmol) and 90%

OAc 196

Mn(acac)3 (10 mol%) under a N2 atmosphere at r.t. 225 b Isolated yields unless otherwise noted. N

c 5 mol% of Mn(acac)3 was used. H

d 224

40 mol% of Mn(acac)3 was used. Me

e N

N d. TiCl

Al c. Me Vinyl azide 62 was recovered in 68% yield. 4 3

Downloaded by: University of Oxford. Copyrighted material.

f 1 83%

The ratio was determined by H NMR spectroscopy, and the major H

TMS H

exo-isomer is shown. 227 82%

g The structures of exo-isomers 205, 209, and 213 were secured by X- 226

ray crystallographic analyses. A proposed mechanism

h Me AcO –

NMR spectroscopic yield, using Cl2CHCHCl2 as an internal stan- Nu

Nu LA

dard, owing to the instability of 211; this product could be isolated as O Lewis acids LA

(LA) N its acetate in 73% yield on treatment of the crude mixture of 211 with N

224

Ac2O (8.0 equiv), Et3N (2.0 equiv), and DMAP (0.1 equiv) in CH2Cl2 H

H H at r.t. for 8 h. 225–227

Scheme 14 196. This one-pot/two-step process represents a straightforward procedure for the construction of the morphan Melinonine-E (228) has been isolated from the bark of framework from readily available vinyl azides and bicy- Strychnos melinoniana,38 and its structure is characterized clic cyclopropanols (Table 11).26a by a unique pentacyclic ring system including indolo[2,3- 39 Further methods for the reduction of the carbon–oxygen a]quinolizidine and morphan frameworks. The first synthesis of (±)-melinonine-E (228) was accomplished by bond at the bridgehead position were explored using ace- 40 tate 224 prepared from alcohol 196 (Scheme 14).26 Inter- Bonjoch and co-workers. We envisaged that the 2-aza- estingly, the titanium(IV) chloride (TiCl ) mediated bicyclo[3.3.1]nonane moiety of melinonine-E (228) could 4 be constructed by the Mn(III)-mediated [3+3]-annulation

32 S. Chiba ACCOUNT

OH of vinyl azide 50 and a bicyclic cyclopropanol bearing a OH

hydroxymethyl-type tether, followed by the reduction of a. Mn(acac)

+ OTBDPS TsN

the carbon–nitrogen double bond and bridgehead carbon– N

H 88%

OTBDPS oxygen bond in intermediate II to give I (Scheme 15). 3 230

50 229 ( exo endo = 85:15)

The construction of the C-ring of melinonine-E (228) was :

planned at a later stage. H

d. LAH, AlCl

N b. Ac O (87%) 3 2

OTBDPS

C-ring

H N

c. TiCl , TES H

construction

C (83%)

E B

A D 231

E D

A N

N H

MeO I MeO

melinonine-E 228

MeO

CHO MeO H H

NaB(OAc) H

OH 3

Mn(III)

H N

E H

D H

B OR A TsN

(R = TBDPS or H) 232

N H [3+3]-annulation

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

f. TBAF N OR 3

93%

: R = H; 12% (from ) 234 231 II

HO Scheme 15 H

g. BBr

3 N H

[3+3]-Annulation of 1-indol-2-ylvinyl azide (50) and bi- H

cyclic cyclopropanol 229 afforded azabicyclic compound 235

230 in 88% yield on a 2-gram scale in a diastereoselective –

ClO

h. maleic acid, H O

manner (exo/endo = 85:15), although 1.6 equivalents of 2

then Pd black N

Mn(acac)3 were needed to complete the reaction OH

then aq NaClO N

26a H

230 H 44% (from ) (Scheme 16). After the conversion of alcohol into 234

melinonine-E its acetate, the bridgehead carbon–oxygen bond was re- 228 duced using the Et3SiH–TiCl4 protocol to afford cyclic Scheme 16 Synthesis of (±)-melinonine-E (228); reagents and con- imine 231. Subsequent reduction of the carbon–nitrogen ditions: (a) 229 (3.0 equiv, added by a syringe pump), Mn(acac)3 (1.6 double bond of 231 with lithium aluminum hydride–alu- equiv), MeOH, r.t., 8 h, 88% yield; (b) Ac2O (8.0 equiv), Et3N (2.0 41 minum trichloride led to not only the entire reduction of equiv), DMAP (0.1 equiv), CH2Cl2, r.t., 12 h, 87% yield; (c) TiCl4 the imine and N-tosyl moieties, but also partial removal of (1.5 equiv), Et3SiH (2.0 equiv), CH2Cl2, r.t., 4 h, 83% yield; (d) AlCl3 the tert-butyldiphenylsilyl (TBDPS) group. Reductive N- (5.0 equiv), LAH (15.0 equiv), r.t., 30 h; (e) (MeO)2CHCHO (1.5 equiv), NaB(OAc)3H (1.5 equiv), CH2Cl2, 0 °C, 30 min, 43% yield of alkylation of the resulting secondary amines of 232 with 233 + 12% yield of 234 (both from 231); (f) TBAF (1.5 equiv), THF, dimethoxyacetaldehyde in the presence of sodium triacet- r.t., 36 h, 93% yield; (g) BBr3 (8.0 equiv), CH2Cl2, –78 °C, 3 h; (h) oxyborohydride provided 233 and 234 in 43 and 12% maleic acid (6.0 equiv), H2O, r.t., overnight, then Pd black (excess), yield, respectively. The remaining TBDPS group in 233 reflux, 50 h; aq NaClO4 (3.0 equiv), r.t., 44% yield (from 234) was removed with tetrabutylammonium fluoride. Boron tribromide induced cyclization of 234 proceeded cleanly to afford cyclic alcohol 235, which underwent dehydra- mation sequence with internal alkynes to construct tion with maleic acid in water followed by dehydrogena- azaheterocyclic frameworks. 42 tion with palladium black in a one-pot manner to afford Downloaded by: University of Oxford. Copyrighted material. It has been revealed that the combined use of [Cp*RhCl2]2 (±)-melinonine-E (228) as a perchlorate salt in 44% yield (Cp* = pentamethylcyclopentadienyl) and metal acetates from 234. The 1H and 13C NMR spectroscopic data of the generates Cp*Rh(OAc)n species and results in deprotona- synthetic (±)-melinonine-E perchlorate were identical to tive carbon–hydrogen bond cleavage with the aid of an in- those previously reported.39,40a tramolecular directing group, such as an imino group, to afford rhodacycles.44,45 The application of this strategy for 2.4 Synthesis of Isoquinolines from a-Aryl-Sub- the synthesis of various kinds of heterocycles has been 46,47 stituted Vinyl Azides and Internal Alkynes studied using reactions with internal alkynes. Based by Rhodium–Copper Bimetallic Cooperation on these background reports, we embarked on our inves- tigation of the reaction of 1-phenylvinyl azide (32) and As mentioned in Section 2.1, vinyl azides readily undergo diphenylacetylene (236) using [Cp*RhCl2]2 as a catalyst

thermal denitrogenation to afford highly strained three-

membered cyclic imines, 2H-azirines, which can be re- 2

N N

garded as vinylnitrene equivalents (Scheme 17). We Δ N

R' – N

turned our attention to the use of these nitrogen atoms de- 2

R' R'

vinylnitrenes H 2 -azirines rived from a-aryl-substituted vinyl azides to direct a metal vinyl azides

N) direct a metal complex complex for ortho C–H metalation, which might be fol- –Can these nitrogens ( to the proximal C–H bond for ortho metallation?

lowed by a carbon–carbon and carbon–nitrogen bond for- – Scheme 17

Synlett 2012, 23, 21–44 © Thieme Stuttgart · New York ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 33 with carboxylate sources (Table 12) to target isoquinoline isomeric mixtures were obtained in the reactions of meta- derivatives.48 While the use of sodium acetate (NaOAc) or substituted substrates, where the less sterically hindered cesium pivalate (CsOPiv) (30 mol%) as a carboxylate carbon–hydrogen bond was cleaved in a preferential man- source did not afford any ortho carbon–hydrogen bond ner (marked in blue) (entries 15 and 16). The construction functionalization product (entries 1 and 2, respectively), of b-carboline, 1H-pyrrolo[2,3-c]pyridine, benzofuro- the reaction with copper(II) acetate [Cu(OAc)2] (20 [2,3-c]pyridine, and benzothiopheno[3,2-c]pyridine mol%) at 110 °C in N,N-dimethylformamide (DMF) gave structures could be achieved using the above process (en- 1-methyl-3,4-diphenylisoquinoline (237) in 70% yield tries 17–20, respectively). The introduction of methyl, sil- (entry 3). The addition of 1 equivalent of AcOH allowed oxymethyl, alkoxymethyl, and aminomethyl groups at the for a lower reaction temperature (90 °C) and catalytic b-position of the vinyl azide did not retard the process and loading of [Cp*RhCl2]2 (2.5 mol%) (entries 5 and 6). No- led to the corresponding isoquinolines in moderate to tably, an acceleration of the reaction rate was observed us- good yields (entries 21–26). ing copper(I) acetate (CuOAc) instead of Cu(OAc)2 (entry To probe how both the rhodium and copper catalysts work 7). in the reaction mechanism, several control experiments were conducted using vinyl azide 32 and alkyne 236 Table 12 Optimization of the Reaction Conditions for the Synthesis 48

of Isoquinoline 237a (Scheme 18).

cat. [Cp*RhCl ] 2 The incorporation of deuterium into the methyl group of 2 2

additive-1 N Ph

N the isoquinoline product to give 279 was observed in the

additive-2

Ph reaction conducted in the presence of water-d (D O) (5 Me 2 2

DMF, conditions

236 equiv) (Scheme 18, part a), whereas this was not observed

(1.2 equiv) 237 32 49

in the reaction using DMF-d7 as a solvent. These results

[Cp*RhCl ]

Additive-2 Additive-1 2 2

Entry Conditions Yield/% suggest that the hydrogen atom at the resulting methyl

/mol% /mol%

/mol% moiety is introduced not via a radical pathway, but in an

1 5 0 NaOAc (30)

110 °C, 12 h ionic manner.

2 5 0 CsOPiv (30)

110 °C, 12 h Next, 2H-azirine 280, prepared by the thermal decompo-

5 70 Cu(OAc) (20) 3 110 °C, 0.3 h

c sition of vinyl azide 32, was subjected to the reaction with

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

AcOH (100) 5 5 90 °C, 0.6 h 80 Cu(OAc) (20) alkyne 236 in the presence of [Cp*RhCl ] and metal ace- 2 2 2

(20) Cu(OAc) 84 6 2.5 AcOH (100) 90 °C, 2 h

2 tates. The reaction with Cu(OAc)2 or CuOAc afforded

2.5 84 CuOAc (20) AcOH (100) 90 °C, 0.5 h 7 isoquinoline 237; no isoquinoline formation was seen with NaOAc at all (Scheme 18, part b). Moreover, the re- a All reactions were carried out using 0.5 mmol of alkyne 236 with 1.2 action with CuOAc was completed within 10 minutes, equiv of vinyl azide 32 under a N2 atmosphere. b Isolated yields, unless otherwise noted, based on alkyne 236. whereas that of Cu(OAc)2 needed 2 hours. The reaction of c NMR spectroscopic yield. vinyl azide 32 with 2 equivalents of CuOAc in the presence of AcOH gave acetophenone (282) in 48% yield, presumably via hydrolysis of the putative N-unsubstituted Using the [Cp*RhCl2]2 (5 mol%)–Cu(OAc)2 (20 mol%) (N-H) imine 281 (Scheme 18, part c). Interestingly, the re- catalytic system, the generality of this method was exam- action with [Cp*RhCl2]2–Cu(OAc)2 under an oxygen at- ined for the synthesis of substituted isoquinolines and oth- mosphere did not afford isoquinoline 237. In sharp 48 er derivatives (Table 13). Wide substrate tolerance was contrast, a carbon monoxide atmosphere promoted the observed with the use of internal alkynes (entries 1–8). isoquinoline formation to give the product in 82% yield Downloaded by: University of Oxford. Copyrighted material. The reactions with diarylacetylenes proceeded smoothly within 0.5 hours (Scheme 18, part d). with vinyl azide 32, giving isoquinolines in good yields (entries 1–3). Dialkylacetylenes also resulted in reason- These experimental results indicated that both rhodium ably smooth reactions (entries 4 and 5). The insertion of (Rh) and copper (Cu) are indispensable for inducing the unsymmetrical 1-phenylprop-1-yne (248) occurred in a ortho carbon–hydrogen bond functionalization of 2H- regioselective manner, affording 1,4-dimethyl-3-phenyl- azirine 280 in the reaction to give product 237. The lower valent Cu(I) species might take part in the reductive ring isoquinoline (249) as the sole product (entry 6). Similarly, 50 methyl 3-phenylpropanoate (250) and 1-(2-thienyl)oct-1- opening of the 2H-azirine to give the imine derivative, yne (252) provided isoquinolines 251 and 253 regioselec- which then might be relayed to initiate Rh(III)-catalyzed tively, albeit in lower yields (entries 7 and 8, respective- ortho C–H rhodation, followed by insertion of the alkyne. ly). The introduction of electron-withdrawing groups as In fact, the ultraviolet/visible (UV/vis) spectra for the substituents on the benzene ring of the a-aryl-substituted treatment of Cu(OAc)2 in DMF at 90 °C showed quench- vinyl azide resulted in isoquinoline formation in good ing of the visible band of Cu(OAc)2 at 700 nm. This observation suggests that a solvent amount of DMF might yields, whereas sluggish reactions were observed from vi- 51 nyl azide 36, bearing the electron-donating methoxy moi- reduce Cu(OAc)2 to form the Cu(I) species. The UV/vis ety (entry 10), as well as from 1-(1-naphthyl)vinyl azide spectra for the treatment of [Cp*RhCl2]2 in DMF at 90 °C (48) (entry 14). Carbon–bromine bonds could be kept in- showed no change of the visible band of [Cp*RhCl2]2 at tact in the synthetic process (entries 3, 12, and 15). Regio- 410 nm.

34 S. Chiba ACCOUNT

N [Cp*RhCl ] (2.5 mol%)

2 2 Table 13 Synthesis of Substituted Isoquinolines and Other Deriva- 2

(20 mol%) Cu(OAc)

2 N

tives from a-Aryl-Substituted Vinyl Azides and Internal Alkynes Cat- N

O (5 equiv) D

a 2

C H D alyzed by [Cp*RhCl ] –Copper(II) Acetate (a) Ph 2 2 Ph n 3–n

DMF, 90 °C, 3.5 h

(n = 1.62) 236

Entry Vinyl azides Alkynes Isoquinolines / yield

32 60% 279

2 R

2 (1.0 equiv) 236

[Cp*RhCl ] (5 mol%)

2 2

1 2

R R

(20 mol%) M(OAc) Me

Ph n

N 2 AcOH (1 equiv)

(b)

1 2

1 , R = 4-MeOC H ) 238 (R 239: 77%

6 4

toluene

1 2

DMF, 90 °C

2 , R = 4ClC H ) 240 (R 241: 70%

6 4

c 1 2

100 °C, 1.5 h

32 time

242 (R 3 , R = 4-BrC H ) 243: 83%

6 4

(1.2 equiv) 280

1 2 82%

, R = n-Pr) 245: 71% 32 244 (R

time M(OAc) 237

1 2

(NMR yield)

= CH OTBS, R = CH OTBS) 247: 54% 32 246 (R

5 2 2

1 2

Cu(OAc) 248 (R = Me, R = Ph) 249: 82% 46% 2 h

32 6

1 2

= CO Me, R = Ph) 251: 27% 250 (R 7

10 min CuOAc 2 52%

1 2 d

32 252 (R = n-hexyl, R = 2-thienyl) 253: 52%

0% 2 h

NaOAc

2 Ph

O CuOAc (2 equiv) N N

H N

AcOH (2 equiv)

Ph Ph

R R DMF, 90 °C

34 (R = Me) 254: 80%

236 9

48% 282

281 36 (R = OMe) 32 255: 45% 236 10

44 (R = CO Me) 236 11 256: 86% 2

257: 80% 236 40 (R = Br)

] (2.5 mol%) [Cp*RhCl Ph 2 2

Ph (20 mol%) Cu(OAc)

N 2 2 Ph

Ph AcOH (1 equiv) N

+ 32 (d)

236

13 258 259: 70% 236 Me

Me DMF, 90 °C

atmosphere

Me 237

N Me Ph

under O 0% N 2

under CO (0.5 h) 82%

236 14 48 260: 38% Ph

Scheme 18 Ph

2 Ph

N N

Me Based on these experimental data, a possible mechanism

R under the [Cp*RhCl2]2–Cu(OAc)2 catalytic system was

261: 74% 262: 12% 42 (R = Br) 236 15

16 236 ) 263: 66% 264: 5% (R = NO 82 proposed, as outlined in Scheme 19. First, the Cu(I) spe- 2

Ph cies is formed via the reduction of Cu(OAc)2 by DMF

N 2

265: 82% 236 17 (step i). 2H-Azirine 280, generated by thermal denitroge-

N 50

Ts native decomposition of vinyl azide 32, is reduced by the

Ph Cu(I) species to afford radical anion A (step ii, path a).

N 2

N N

236 266: 77%

18 Ring opening by carbon–nitrogen bond cleavage of A

N 52

Ts forms iminylcopper(II) radical intermediate B, which is

Ph further reduced with Cu(I) and protonated to give N-H

N 19

268: 45% N

236 imine 281 along with the Cu(II) species. Alternatively, it O

267 O

Me can be proposed that the direct reduction of vinyl azide 32

N by the Cu(I) species forms the putative radical intermedi-

2 236 269: 75%

20 Ph

S ate B via vinyl azide radical anion E (step ii, path b). The S

2 formation of rhodacycle G from N-H imine 281 or iminyl- R R

2 2 Downloaded by: University of Oxford. Copyrighted material. R

e 1 2

N 62 21 , R = Ph) (R 236 D F 85% 270: copper intermediate with Rh(III) via iminyl rhodium ,

e 1 2

62 22 , R = n-Pr) 244 (R 271: 54%

1 2

e followed by insertion of alkyne 236 and subsequent car- 62 23 = Me, R = Ph) 248 (R 272: 80% Me

Me bon–nitrogen bond formation through reductive elimina-

N 2

Ph tion from H, provides isoquinoline 237 with the N

274: 46% 236 24 273 (R = TBDPS)

: 40%

276 generation of the Rh(I) species (step iii). Finally, a redox 275 (R = CH CH=CH ) 25

236 2 2

OR reaction between the Rh(I) and Cu(II) species leads to the OR

Ph regeneration of Rh(III) and Cu(I) (step iv).

N N

O O 236 277

278: 85% 26 The reductive formation of imine derivatives from vinyl

N azides is supposed to proceed via the protonation of cop-

O O per(II) azaenolates, such as C (Scheme 19, step ii). We aimed to trap such putative azaenolates with other electro- a The reactions were carried out by treating a mixture of the vinyl philes for the further functionalization of isoquinoline de- azide (1.2 equiv) and alkyne (0.5 mmol) with [Cp*RhCl2]2 (5 mol%) rivatives. After the extensive screening of various and Cu(OAc)2 (20 mol%) in the presence of AcOH (1 equiv) in DMF electrophiles, it was found that the addition of TEMPO (2.5 mL) at 90 °C under a N2 atmosphere for 1–2 h. b Isolated yields unless otherwise noted. (2,2,6,6-tetramethylpiperidin-1-yloxyl) (2 equiv) instead c 1.5 equiv of vinyl azide 32 were used. of AcOH in the reaction of vinyl azides 62 and 277 with d NMR spectroscopic yield. several alkynes under the [Cp*RhCl2]2–Cu(OAc)2 cata- e 2.5 mol% of [Cp*RhCl2]2 was used. lytic system delivered isoquinoline–TEMPO adducts and f 10 mol% of [Cp*RhCl2]2 was used.

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

ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 35

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

2 Table 14 Reaction of Vinyl Azides and Internal Alkynes with

O 2,2,6,6-Tetramethylpiperidin-1-yloxyla

[Cu ]

Cu (OAc) H N 2

(DMF)

[Cp*RhCl ] (2.5 mol%)

2 2

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

(20 mol%) Cu(OAc) 2

2 3

+ +

N R R

N path a

DMF, 90 °C, 1 h

[Cu ]

[Cu ] H N

R N N N

(2 equiv) (1.5 equiv)

Ph Ph Me

– N

3 3

R R

280 32 281

2 2

R R

+ N N [Cu ] N [Cu ] H

H O O

[Cu ]

[Cu ] [Cu ]

[Cu ]

1 1

H R R

[Cu ]

N N N

TEMPO adducts alcohols

[Cu ]

– N

Ph Me Ph Ph 2 – [Cu ]

TEMPO B D C

E path b Alkynes

Alcohols Entry Vinyl azides

b adducts

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

Ph Ph

1 : 68% 283 : 15% 284 N

III

236 III

[Rh ] [Rh ]

III

[Rh ]

236

H N N

n n -Pr -Pr

Ph 2 : 39% 285 : 42% 286

III

[Rh ]

244

Me Me Me

or 281 D

+ – H

or – H

H G : 55% 287 3 : 18% 288 F

Me Ph – Cu(II)

237 248

I N 2 – [Rh ]

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

II I

I III

+ +

2 [Cu 2 [Cu ] ] [Rh ] ] [Rh [Rh] = Cp*Rh(OAc) n

c : 48% 289 : 29% 290 Ph Ph 4

Scheme 19 236 277

48,52 alcohols in good combined yields (Table 14). From vi- a All reactions were carried out using 0.5 mmol of the alkyne with 1.5 nyl azide 277, a b-amino alcohol unit could be installed in equiv of the vinyl azide under a N2 atmosphere. the isoquinoline framework (entry 4). Although we are b Isolated yields are shown based on the alkyne. not certain as to the reaction mechanism of this carbon– oxygen bond formation, one possibility might be the nu- As expected, the catalytic conversion of 2-azidocyclobu- cleophilic attack of the azaenolate carbon to a Cu(II)– tanols proceeded smoothly with Mn(pic)3 to give the cor- TEMPO complex, which would act as an ionic electro- responding pyrroles 291–293 in excellent yields,54 phile. whereas that of 2-azidocyclopentanol or -cyclopentenol derivatives was unsuccessful (Scheme 21).55 This sug- gested that the release of the ring strain is indispensable as 3 Chemistry of Cyclic 2-Azido Alcohols a key driving force of this Mn(III)-catalyzed b-fission strategy. 3.1 Manganese(III)-Catalyzed Ring Expansion

of 2-Azidocyclobutanols

Following the above-mentioned formal [3+2]- and [3+3]- O

(10 mol%)

O 3

annulation strategies of vinyl azides via an iminylmanga- N

Downloaded by: University of Oxford. Copyrighted material. MeOH, 0 °C, 0.5 h R

nese(III) species as a key intermediate, we planned an al- then 40 °C, 3 h

N 291 (R = H); 90%

292 (R = Me); 88%

ternative method for generating such metal species using N 2 (R = Cl); 89%

the metal-mediated b-fission (b-carbon elimination) of 293

53 OH

cyclic 2-azido alcohols. As shown in Scheme 20 as an Mn(III)

no reaction

N N

example, the oxidative b-fission of 2-azidocyclobutanol 2 or -cyclopentanol would provide iminyl radical/metal 0% species along with the formation of an intramolecular car- Scheme 21 bonyl moiety, which would cyclize to afford the corresponding heterocycles, such as pyrrole (n = 1) or pyridine (n = 2), respectively. 3.2 Palladium(II)-Catalyzed Ring Expansion of

Cyclic 2-Azido Alcohols

O O OH n ]

[M Further extensive investigations revealed that a palladi-

n–1 n

] – [M

N N N N N N N N N um(II) [Pd(II)] catalyst system could achieve the ring-expansion reaction of nonstrained cyclic 2-azidopentenol

O derivatives.56 The reaction involves an unprecedented car-

or 57 N

– N N

n bon–carbon bond cleavage and carbon–nitrogen bond 2 H

N (n = 1) (n = 2) formation sequence to provide azaheterocycles, such as pyridine and isoquinoline derivatives. Scheme 20

36 S. Chiba ACCOUNT

As a model substrate, (1R*,5R*)-5-azido-2,3-diphenylcy- OH

Ph Ph Ph

clopent-2-enol (trans-294) was selected, and its reactions N

N N N

Ph [Pd ]

under Pd catalyst systems (with 1 equiv of K2CO3 in Ph

H O 294 295 IV

DCE) were examined.56 While Pd(II) complexes them- 2

+ +

[Pd ]

H H

II selves did not exhibit any reactivity, they showed interest- O O [Pd ]

ing catalytic effects in the presence of phosphine and Ph

N N N

nitrogen ligands, giving the ring-expansion product 3,4- II

[Pd ]–OH

Ph Ph

diphenylpyridine (295) (Scheme 22). Extensive ligand III

O [Pd ]

screening revealed that bidentate ligands worked effi- Ph

N ciently with Pd(II) catalysts for the pyridine formation, 2

Ph and the use of PdCl2(dppf) [dppf = 1,1¢-bis(diphenylphos- II phino)ferrocene] (15 mol%) at 80 °C gave 295 in the best Scheme 23 yield (88%). Interestingly, Pd(OAc)2 with bidentate nitrogen ligand 2,2¢-bipyridine also exhibited good catalytic activity. The reactions of the corresponding cyclic cis-2- chlorine and carbon–bromine bonds, respectively, intact. azido alcohol cis-294 also proceeded to form pyridine 3-Arylpyridines with some substituents were available us- 295, although the yield of 295 was lower than that from ing this method. trans-294. It was also noted that other metal complexes, This catalytic ring expansion could be applied to the syn- such as nickel(II), Cu(I), Rh(I), and gold(I) complexes, thesis of substituted isoquinoline derivatives from the cor- were not viable catalysts for this transformation. responding azidoindanols (Table 16).56 It should be noted

that the reactions of both trans-1-azidoindan-2-ol and

Pd catalyst, ligand trans-2-azidoindan-1-ol derivatives afforded the same

CO (1 equiv) K

2 3

N isoquinolines. Interestingly, the reactions of the 2-azido-

N 3

DCE

Ph indan-1-ol derivatives, such as 312 and 315, proceeded at

80 °C

295

trans -

294 room temperature using a Pd(OAc)2–dppf system to give

PdCl (dppf) (15 mol%), 5 h 88%

2 the products in excellent yields. Both electron-withdraw-

Pd(OAc) –2,2'-bipyridine (15 mol%), 0.5 h 80% 2 ing and electron-donating groups were incorporated on

the isoquinoline ring. Chloro substituents on the benzene

PdCl (dppf) (15 mol%)

OH ring were tolerated. Azido alcohols bearing a phenyl 2

CO (1 equiv) K

2 3

N group at C-3 or C-2, such as in 322 and tertiary alcohol

N 3

DCE

Ph 324, respectively, were converted into the corresponding Ph

80 °C, 4 h

59% 295 cis - 294 isoquinolines in good yields. Moreover, this method also afforded g-carboline 327 from substrate 326. Scheme 22 Optimized reaction conditions for the palladium-cataly-

zed ring expansion of cyclic 2-azido alcohols Table 15 Synthesis of Pyridines from Cyclic 2-Azido Alcoholsa,b

PdCl (dppf) (15 mol%)

1 1

CO (1 equiv) K

R R 2 3

As shown in Scheme 23, the catalytic cycle could be ini- N

DCE 2

b R tiated by -carbon elimination of palladium(II) alcoholate 2 R

I, generated from azido alcohol 294 with a Pd(II) complex 80 °C

R Me

in the presence of a base. It was speculated that this pro- N

Me Downloaded by: University of Oxford. Copyrighted material. cess might be promoted by the coordination of the internal N

nitrogen of the azido moiety to the metal center.58 The

subsequent elimination of molecular nitrogen provides Me

299: 83% 300: 74% 301: 80% ; R = Me: 78%

iminylpalladium(II) species II, which undergoes intramo- 296 297; R = Cl: 88%

; R = F: 89%

lecular nucleophilic attack to the resulting carbonyl group, 298

305; R = H: 83%

N Me R

affording cyclized intermediate III. Protonation of III fol- N 306; R = Me: 64%

307; R = Cl: 84% lowed by dehydration affords pyridine 295 along with the N

308; R = F: 86%

; X = Cl: 90%

Pd(II) complex. Alternatively, elimination of a hydroxi- 303

: 93% 309; R = CF

302: 65% c

; X = Br: 72% dopalladium(II) species from III provides 295 directly. 304

The generality of this catalytic ring expansion for the syn- a Unless otherwise noted, the reactions were carried out using 0.3 thesis of substituted pyridines was next examined using mmol of the azido alcohol in the presence of 15 mol% of PdCl2(dppf) 56 trans-azido alcohols (Table 15). The method allowed and 1 equiv of K2CO3 in DCE (2 mL) at 80 °C under a N2 atmosphere. the installation of not only aryl substituents, but also me- b Isolated yields are shown next to the corresponding products. c thyl and allyl groups at C-3 of the pyridine ring. 3,4-Di- The reaction was run using 10 mol% of Pd(OAc)2 and 2,2¢-bipyri- alkyl-substituted pyridine 302 could also be synthesized dine as a catalyst. d 20 mol% of PdCl (dppf) was used. in good yield. Importantly, 3-chloro- and 3-bromopy- 2 ridines 303 and 304 could be prepared with the carbon–

Synlett 2012, 23, 21–44 © Thieme Stuttgart · New York ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 37

Table 16 Synthesis of Isoquinolines and g-Carbolinea,b 1).62 The reaction could also be used to install methyl and

b b

Products (yield/%) Products (yield/%) trans trans -Azidoalcohols -Azidoalcohols benzyl groups, as well as some cycloalkyl moieties and an

X alkene tether, at the C-3 position of the isoindole (entries

3 EtO C

MeO C

Cl 2 N

N 2–8). The reaction of azide 344 bearing a 4-toluoyl group Y

OH instead of ethoxycarbonyl also proceeded smoothly to

(X = N 310 , Y = OH) (81) 311

(90) 321

320

) (96) (X = OH, Y = N 311 312 give 1-toluoylisoindole 345 in 85% yield (entry 9). A flu- 3

X orine or bromine atom could be introduced at the C-5 or

3 O

N C-4 position of the isoindole ring (entries 10 and 11, re-

O spectively). It is noteworthy that 6H-pyrrolo[3,4-b]pyri-

(X = N 313 , Y = OH) (76) 314 Ph 3

Ph 322 (73) 323 ) (92) (X = OH, Y = N 314 315 dine 351 was readily accessible using this method (entry

3 12). OH N

MeO

N MeO

N Following this discovery of the formation of isoindoles

Ph Cl

(62) 325 (96) 317 316 324 via azide–alkene 1,3-dipolar cycloaddition, it was found

Me that the treatment of azide 328 with potassium carbonate OH OH

Ph Ph

N (K2CO3) (5 equiv as a base) and EtOH (10 equiv as a pro-

N N

3 3

N ton source) in 1,3-dimethylimidazolidin-2-one (DMI) (0.3

326 (93) 327 (90) 318 319 Me

Me Table 17 Synthesis of Isoindole Derivatives from a-Azido Carbon- a a Unless otherwise noted, the reactions were carried out using 0.3 yl Compounds

mmol of the azido alcohol in the presence of 15 mol% of PdCl (dppf)

2 b Entry Azides Isoindoles

and 1 equiv of K2CO3 in DCE (2 mL) at 80 °C under a N2 atmosphere. Yield

1 2 1

R R

b R

2 Isolated yields are shown next to the corresponding products. 1

(R 328 , R = Me) 1 98% (83%)

c 329

The reaction was carried out using 10 mol% of Pd(OAc)2 and 10 1 (R 330 94% (75%) 331 , R = H) 2

1 2 c

NH (R 332 = Ph, R = H) (99%) mol% of dppf at r.t. 333 3

d 3

= 4-MeOC H

20 mol% of PdCl (dppf) was used. R 4

2 6 (87%) 335

334

CO Et

2 CO Et = H R 2

( )

( ) n

(n = 4) 336 5 (87%)

4 Chemistry of a-Azido Carbonyl Compounds 337 (n = 2) 338 6 (70%) 339

N (n = 1) 340 7 (54%) 341 3

CO Et

CO Et 2 4.1 Orthogonal Synthesis of Isoindole and Iso- 2 quinoline Derivatives

Isoindoles and their derivatives are attractive candidates

8 82% 343 342

NH for organic light-emitting devices (OLEDs) owing to their N

good fluorescent and electroluminescent properties.59 3

CO Et CO Et 2 2

Me They show high reactivity in [4+2] cycloadditions with Me

various dienophiles for the preparation of oligoacenes.60 Me

345 85% 9 344 NH We envisaged that the intramolecular azide–alkene cy- N

61 a 3 p -Tol cloaddition reaction of readily available -azido carbon- CO p -Tol

yl compound 328, bearing a 2-alkenylaryl moiety at the a- CO Me Me Me

position, and the subsequent elimination of molecular ni- Me

Downloaded by: University of Oxford. Copyrighted material. F F

10 346 347 (82%) trogen from the resulting triazoline would produce isoin- NH N

dole 329, as shown in Scheme 24. 3

CO Et

CO Et 2

The expected isoindole formation proceeded smoothly on Br Br

heating azide 328 in toluene (0.1 M concentration) at 100 Me

348 349 (57%) 11 NH

°C, giving isoindole 329 in 98% yield (Table 17, entry N 3

CO Et

CO Et 2

Me Me

Me Me Me Me

12 2 351 (61%) 350

Δ NH

N N

N N 3

azide–alkene

CO Et

cycloaddition

CO Et

CO Et 2 triazoline

328 a

Me The reactions were carried out by heating the azide in toluene (0.1 Me

Me Me M) at 100 °C for 3 h.

b In parentheses is the two-step yield from the corresponding mesy-

NH N

– N late. In this case, the product was obtained by treating the mesylate 2

CO Et

CO Et 2 with NaN (1.2 equiv) in DMF (0.3 M) at 0 °C, followed by workup 2 3

329 isoindole and then heating the resulting crude azide in toluene (0.1 M) at 100 °C for 3–5 h. Scheme 24 c Z/E = 5.4:1.

M concentration) at 40 °C induces denitrogenation to pro- sponding 4-methylisoquinoline 379 in 65% yield (entry vide N-H imine 352.63 Subsequent 6p-electrocyclization64 11). of the resulting azahexatriene moiety of 352 was observed to be promoted by diluting the concentration with toluene 4.2 Generation of Iminylcopper Species and (0.1 M) and heating at 100 °C, giving dihydroisoquinoline Their Catalytic Carbon–Carbon Bond 353 in 95% yield (Scheme 25, part a). Based on this find- Cleavage under an Oxygen Atmosphere ing, the direct transformation of mesylate 354 into dihydroisoquinoline 353 was also achieved in 90% yield on Based on the above-mentioned isoquinoline formation via treatment of 354 with sodium azide (1.2 equiv), K2CO3 (5 N-H imine intermediates, we next explored the generation equiv), and EtOH (10 equiv) in DMI at 40 °C, followed by 352 Table 18 Synthesis of Isoquinoline and Dihydroisoquinoline De- cyclization of the resulting imine in toluene–DMI at a

100 °C (Scheme 25, part b).62 rivatives

Mesylate Entry Isoquinolines (yield/%)

Me Me

K CO (5 equiv)

2 3 1 355 356 (82)

OMs

N Me

EtOH (10 equiv) add toluene 2

H N

CO Et CO Et

2 2 (0.1 M)

DMI (0.3 M)

CO Et 100 °C, 8 h

40 °C, 1 h CO Et

CO Et

Ar 352

328 95% 353 (a)

OMs N N

Me Me

NaN (1.2 equiv)

3 CO Et

CO Et

CO Et 2

Me 2

CO (5 equiv) K

2 3

(52) (16) 358 359 357 (Ar = Ph) 2 Me EtOH (10 equiv) add toluene

imine

(50) 361 3 360 (Ar = 4-MeOC H ) (14) 362

6 4

352

OMs

(0.1 M) DMI (0.3 M)

CO Et 100 °C, 8 h

2 40 °C, 1 h

CO Et (b)

90% 353

354

363 4 364 (96) N

Scheme 25 OMs

CO Et CO Et 2 2

365 This method resulted in the synthesis of a range of struc- 5 N N

turally diverse isoquinoline and dihydroisoquinoline de- OMs

CO Et

2 2

CO Et

62 2

367 (13) (71) rivatives from the corresponding mesylates (Table 18). 366

From mesylate 355 bearing a vinyl group, the 6p-cycliza-

368

6 (88) tion followed by oxidation of the resulting dihydroiso- 369 OMs

quinoline under an oxygen atmosphere gave ethyl N

CO Et CO Et 2

isoquinoline-1-carboxylate (356) in 82% yield (entry 1). 2

Me Me

The reaction of styryl derivative 357 afforded 3-phenyl- Me Me

370 371 (78) 7 N

isoquinoline 358 in 52% yield along with 4-phenyliso- OMs

COp-Tol

p-Tol quinoline 359 (16% yield), which may have been formed CO

via rearrangement of the phenyl group during the aerobic Me

373 (89) 8 372 oxidation of the dihydroisoquinoline (entry 2). However, Me OMs

mesylate 360 bearing a 4-methoxyphenyl group, which N

CO Et CO Et 2

has a higher migratory aptitude than a phenyl group, gave Downloaded by: University of Oxford. Copyrighted material. Br

a nearly identical distribution of products (entry 3). Dihy- Br

375 (79) 374

droisoquinoline 364 bearing a spirocyclohexane moiety 9 OMs

was successfully prepared in excellent yield from the N

CO Et CO Et 2

corresponding mesylate 363 (entry 4). Mesylate 365 2

Me Me

Me possessing a cyclobutylidenemethyl moiety gave spiro- Me

377 (77) 10 376

OMs

dihydroisoquinoline 366 in 71% yield along with 13% N N

CO Et

Et yield of 3-propylisoquinoline 367, formed via ring open- CO 2

ing of the cyclobutane moiety/aromatization (entry 5). Me

b 379 (65) The cyclopropane moiety, however, could not be kept in 378 11

the corresponding reaction of 368 which resulted in only OMs

CO Et

CO Et 2 3-ethylisoquinoline 369 in 88% yield (entry 6). Neither 2 the replacement of the ethoxycarbonyl moiety with a 4-toluoyl group nor the introduction of halogen atoms on a Unless otherwise noted, the reactions were carried out by treating the aryl ring retarded the process (entries 7–9). In addi- the mesylate with NaN3 (1.2 equiv), K2CO3 (5 equiv), and EtOH (10 377 equiv) in DMI (0.3 M) at 40 °C for 1–3 h, followed by the addition of tion, 1,7-naphthyridine framework could be con- toluene (0.1 M) and then heating at 100 °C for 8 h. structed in good yield (entry 10). The reaction of mesylate b After the consumption of the imine, the mixture was purged with O2 378 bearing a 1-methylvinyl group delivered the corre- and heated at 100 °C. c Z/E = 5.4:1.

Synlett 2012, 23, 21–44 © Thieme Stuttgart · New York ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 39 of iminylmetal species by trapping N-H imine 352 with resulting arenecarbonitriles, such as in products 382–388 transition metals and we looked at their chemical reactiv- and 389–394, respectively. Halogen atoms, such as bro- ity. During the course of this study, it was found that the mine and fluorine, were also introduced into the products treatment of N-H imine 352, generated from azide 328, with the reaction keeping the carbon–halogen bond intact, with 1 equivalent of Cu(OAc)2 at 60 °C under an argon at- as in the formation of 389–392. In addition, alkanecarbo- mosphere afforded unexpected benzonitrile 380 in 32% nitriles were synthesized using sodium ethoxide as a base. yield instead of isoquinoline 353 (Scheme 26).65 It was In particular, the formation of tertiary carbonitriles 395 supposed that benzonitrile 380 was formed via oxidative and 396 proceeded in good yields, whereas the reactions carbon–carbon bond cleavage between the imino carbon to form secondary and primary carbonitriles 397 and 398, and the ethoxycarbonyl carbon of the putative iminylcop- respectively, were sluggish. per intermediate A.

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

Me Me

Cu(OAc) (20 mol%)

Cu(OAc) Me

K CO (5 equiv)

2 3

CO (1 equiv) K N

2 3

(1 equiv)

EtOH (10 equiv)

N R C N Me

R CO Et

DMF (0.1 M), 60 °C

H N

60 °C, 27 h

DMI, 40 °C, 1 h

under O (1 atm)

under Ar

CO Et

2 CO Et 2

352 arenecarbon nitriles 328

Me Me

CN Me Me

: R = 4-Br (85%) 389

(90) 382

(47%) (93%)

: R = 4-C : R = 2-Br 385 H 390

6 5

c,d

(62%) (90%)

: R = 3,5-Br 391 : R = 4-OMe 386 N [Cu]

N C (75%) : R = 2-OMe 387 (49%)

: R = 3,5-F 392

CO Et 32% 380 (87) 384 (70%)

: R = 3,4-(OMe) (72%) 388 : R = 4-CN 393 2 2

c,e

: R = 4-CO 394 Me (81%) 2 f

Scheme 26 alkanecarbon nitriles Me Me

CN CN

Ph CN

(91%) 395 (37%) 398 (64%) (28%) 397 The optimization of this benzonitrile formation was inves- 396 tigated using ethyl 2-azido-2-(2-naphthyl)acetate (381) 65 a (Scheme 27). Treatment of 381 with Cu(OAc)2 (1 equiv) The reactions were carried out using 0.3 to 0.55 mmol of the azide. b and K2CO3 (1 equiv) in DMF at 60 °C directly delivered Isolated yields are shown in parentheses next to the corresponding 2-naphthonitrile (382) in 78% yield along with 3% yield products. c of a-keto ester 383, which is likely formed by the hydrol- The reactions were run by treating the corresponding bromide (for ysis of the corresponding iminylcopper or N-H imine in- 391) or mesylate (for 392–394) with NaN3 followed by Cu(OAc)2 and K2CO3 under O2 (1 atm). termediate. In this case, the coordination of Cu(OAc) to d 2 40 mol% of Cu(OAc)2 was used at 80 °C. the internal nitrogen of the azido moiety might induce the e A methyl ester was used as the starting material. denitrogenative formation of the corresponding iminyl- f 1 equiv of NaOEt was used as a base. copper. A catalytic amount of Cu(OAc)2 under an argon atmosphere could not complete the reaction. In sharp con- In the reaction of substrate 399 bearing a biphenyl-2-yl trast, the reaction was dramatically accelerated under aer- group with 40 mol% of Cu(OAc)2, benzonitrile 400 was obic conditions. Under an oxygen atmosphere (1 atm), formed in 55% yield along with 41% yield of phenanthri- nitrile 382 was obtained in 90% yield using 20 mol% of dine 401, which was presumably synthesized by carbon– Cu(OAc)2. nitrogen bond formation involving an aromatic carbon– Downloaded by: University of Oxford. Copyrighted material.

hydrogen bond and a putative iminylcopper species

2 65,66

Cu salts O

N (Scheme 28). The stoichiometric use of Cu(OAc)2 im-

CO (1 equiv) K

2 3 CN

Et CO Et CO proved the yield of benzonitrile 400 to 74% (formed along 2 2

DMF (0.1 M), 60 °C with 20% yield of 401).

atmosphere

383 381 382

78%

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

2 2

11% 12%

CO (1 equiv) K N Cu(OAc) (20 mol%) under Ar (24 h) N 2 3 2

90% 3%

Cu(OAc) (7.5 h) (20 mol%) under O

2 2

CO Et

CO Et 2 2 DMF (0.1 M), 60 °C

under O (1 atm)

Scheme 27 Optimized reaction conditions for the nitrile formation 2 400 401 399

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

100 mol% of Cu(OAc)

74% 20% With the optimized conditions in hand, the generality of 2 this catalytic method was examined for the synthesis of Scheme 28 carbonitriles using a-azido esters (Table 19).65 The process provided the decarboxylated, one-carbon-shorter carbonitriles from the corresponding carboxylic acid To probe the reaction mechanism of this catalytic cycle derivatives. The reaction allowed the installation of both with a special interest in the identification of any co-prod- electron-donating and electron-withdrawing groups in the ucts derived from the carbonyl fragment after carbon– carbon bond cleavage and the role of the molecular oxy-

© Thieme Stuttgart · New York Synlett 2012, 23, 21–44 40 S. Chiba ACCOUNT gen, substrates 402 and 404 were employed in the above bonyl compound on elimination of molecular nitrogen via catalytic carbonitrile formation (Schemes 29 and 30, re- the deprotonation of I. The oxidation of II with oxygen af- spectively).65 fords peroxycopper(III) species III, which adds to the in- The reaction of 2,4,4-trimethyl-1-pentyl ester 402 afford- tramolecular carbonyl group to induce carbon–carbon ed 2-naphthonitrile (382) and 2,4,4-trimethylpentan-1-ol bond cleavage delivering the carbonitrile and (acylper- (403) in 81 and 72% yield, respectively (Scheme 29). oxy)copper IV. Protonation of (acylperoxy)copper species IV provides carboxylic acid V with the regeneration Interestingly, the treatment of a-keto azide 404 provided of the Cu(II) salt. When ester substrates are used, further benzonitrile 386 and the corresponding benzoic acid 405 decarboxylation of V proceeds to afford the correspond- 18 (Scheme 30, part a). The use of isotope oxygen ( O2) re- ing alcohols. vealed that one of the oxygen atoms from the molecular oxygen is incorporated into the benzoic acid. The reaction The stoichiometric reaction under an argon atmosphere of 404 in the presence of styrene (406) (1 equiv) under the (see Scheme 27) indicated that iminylcopper(II) II could catalytic conditions gave benzonitrile 386 (76% yield) form the carbonitrile and acylcopper VI by b-carbon elim- and benzoic acid 405 (54% yield) along with styrene ox- ination as another mechanistic possibility (Scheme 32, ide (407) in 9% yield (analyzed by GC) (Scheme 30, part path a). In addition, it could also be speculated that peroxy- b). This indicated that an (acylperoxy)copper species67 copper III undergoes b-fission to lead to the formation of might be involved in the catalytic cycle. the carbonitrile and acylcopper VII, which isomerizes to

(acylperoxy)copper IV (path b).

N Cu(OAc) (20 mol%) 3 2

CO (1 equiv) K path a O

2 3

[Cu ]

DMF (0.1 M), 60 °C

II 2 N

[Cu ] R 2

72% under O (1 atm) 403 81% 382

III 2 402 2

2 [Cu ] R R

R O

–CN

Scheme 29 R

VII

II 2

O [Cu ] R

O 2 O

O Cu(OAc) (20 mol%) OMe

III

O [Cu ]

path b

CO (1 equiv) K

2 3

N R –CN

1 DMF (0.1 M), 60 °C

III

MeO

O ( ) (1 atm) under O

2 2 (a) 404

OMe

CN Scheme 32

MeO ) O ( O

81% 386

63%

405 4.3 Copper(II)-Catalyzed Aerobic Synthesis of

Cu(OAc) (20 mol%)

2 Azaspirocyclohexadienones +

54% 405 76% 386

CO (1 equiv) K

2 3

(b) Ph +

404

O To further broaden the substrate scope of the above-men-

406 +

DMF (0.1 M), 60 °C

(1 equiv)

under O (1 atm)

2 9% 407 tioned Cu(II)-catalyzed aerobic carbonitrile formation, the reactions of a-azido amides were tested. The morpho- Scheme 30 line-derived amide 408 provided the corresponding car-

bonitrile product, 2-naphthonitrile (382), in good yield

2 (Scheme 33), although a longer reaction time (36 h) was

2 Downloaded by: University of Oxford. Copyrighted material.

2 N

R required compared with that for the synthesis from esters

2 2

R H–R

II = alkoxy)

(R (see Scheme 27).

[Cu ]

V O

Cu(OAc) (20 mol%)

[Cu] O N 2 3

CO (1 equiv) K N CN

2 3 2

II 2

O [Cu ] R

[Cu ]

O N

O Ar

DMF, 60 °C

under O (1 atm)

R 2

382 73% IV

408

I 36 h

III

[Cu ]

O Scheme 33

O N

N , H 1

2 R C N 2

1 R R

O O N-Phenyl-substituted amide 409 was next subjected to 20

II III mol% of Cu(OAc)2 in the presence of potassium phos- Scheme 31 phate at 80 °C under an oxygen atmosphere to confirm the co-product after the expected carbon–carbon bond cleavage (i.e., N-methylaniline) (Scheme 34).68 In this case, the Based on these results, a mechanism for this aerobic reaction was complete within 4 hours and, surprisingly, Cu(OAc)2-catalyzed carbonitrile formation was proposed, azaspirocyclohexadienone 410 was isolated in 77% yield as shown in Scheme 31. In this possible mechanism, im- without any observation of the carbon–carbon bond cleav- inylcopper intermediate II is formed from the a-azido car-

Synlett 2012, 23, 21–44 © Thieme Stuttgart · New York ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 41

18 age. The use of O2 revealed that one of the oxygen atoms Table 20 Copper(II) Acetate Catalyzed Synthesis of Azaspirocy-

from molecular oxygen is installed in the resulting carbo- clohexadienonesa,b

nyl group of azaspirodienone 410. The reaction with 1 O

3 Cu(OAc) (20 mol%)

N 2

equivalent of Cu(OAc) under an argon atmosphere ex- R

2 3

PO (1 equiv) K R

3 4 N

clusively provided a-keto amide 411, which was formed N

2 N

1 N-R

2 R

DMF, 80 °C R

via hydrolysis of the corresponding iminylcopper species R O under (1 atm) O

or N-H imine. O

O O O

MeO MeO

( ) O O OMe

Cu(OAc) (20 mol%)

N N 2 NMe

NPh

PO (1 equiv) K NMe NMe

3 4

R N

Ph Ph Ph

O NMe O O

DMF, 80 °C, 4 h

: R 412 = 3,5-Me C H ; 78% Me 2 6 3

1 : 77% 426

: 60% 425 : 60% 424

( O )

under O

= 4-PhC H ; 75% : R 413 2 2 6 4 O

1 (1 atm) = 2-naphthyl; 83% : R 414

1 c

Me 77% 410 = 1-naphthyl; 55% : R 415

Me 409

1 d

: R 416 = 4-MeOC H ; 65% Me Me 6 4

: R 417 = 4-ClC H ; 81% 6 4

1 Cu(OAc) (100 mol%)

: R = 4-BrC H ; 80% 418

6 4 NMe

PO (1 equiv) K

3 4

: R = 3,5-F C H ; 76% 419

2 6 3

Ph Ph

409

: R = 3,5-(F C) C H ; 65% 420 O

O Me 3 2 6 3

DMF, 80 °C, 4 h

: R = 4-NCC H ; 69% 421

6 4

O : 72% 428

: 75% 427 under Ar

1 e

: R = 1-adamantyl; 29% 422

68% 411

1 e,f : R 423 = Me; 0% Scheme 34 a The reactions were carried out using 0.5 mmol of the a-azido amide The spirodienone structures have commonly been con- with 20 mol% of Cu(OAc)2 and 1 equiv of K3PO4 in DMF (0.1 M) at 80 °C under an O2 atmosphere. structed by the oxidative treatment of phenol deriva- b Isolated yields are shown next to the corresponding products. tives.69,70 This unprecedented and mechanistically c 1-Naphthonitrile and N-methylaniline were also obtained in 21 and intriguing formation of azaspirodienones, as well as the 19% yield, respectively. potential pharmaceutical properties of their derivatives,71 d 4-Methoxybenzonitrile and N-methylaniline were also obtained in 27 and 12% yield, respectively. drove us to explore the substrate scope of our reaction e 68 1 NaOMe (1 equiv) was used as a base. (Table 20). By varying substituent R , aryl rings bearing f N-Methylaniline was obtained in 45% yield. various groups (regardless of their electronic nature) could be introduced, as in the formation of 412–421. This process could also keep carbon–halogen bonds intact, nation of I occurs, which is followed by the oxidation of such as those in the reactions to give 417–420. Alkyl II with molecular oxygen to form peroxycopper(III) III. 1 groups as R , such as those in 422 and 423, were not via- The formation of azaspirocyclohexadienol in the reaction ble for this transformation. Azaspirodienones 424, 425, of N-4-tolylamide 432 (Scheme 35, part b) indicates that 427, and 428 bearing electron-donating substituents on the intramolecular imino-cupration of III might occur to the cyclohexadienone ring were formed in good yields. In form carbon–nitrogen and carbon–copper bonds concur- 2 addition to methyl as substituent R on the amide nitrogen, rently at the ipso- and para-positions of the benzene ring,

phenyl and benzyl groups could be used, such as in the synthesis of 426 and 428, respectively. O

Downloaded by: University of Oxford. Copyrighted material.

Cu(OAc) (20 mol%)

During the course of this study, the reactions of certain 2 Me

NaOMe (1 equiv)

N (a)

substrates gave significant mechanistic information. The +

NMe N Me

Ar Me DMF, 80 °C

reaction of azide 429, sterically hindered by a 2,6-dimeth- O

O (1 atm) under O Me 2 O

429 431 36% 25% ylphenyl group, afforded azaspirodienone 430 in 25% 430

yield along with N-phenylimine 431 in 36% yield (Ar = 2,6-dimethylphenyl)

(Scheme 35, part a). The latter compound could be Me

Me H

formed by the transfer of the phenyl group from the amide O

nitrogen to the imine nitrogen via an intramolecular ipso- + N N

NMe

substitution reaction of the corresponding iminylcopper. NMe

Ph Ph Me

Interestingly, the treatment of N-4-tolyl amide derivative O

Cu(OAc) (20 mol%)

433-(5 R R *,8 *) S S *,8 *) 433-(5

PO (1 equiv) 432 under the catalytic conditions afforded diastereomers K

3 4

18% 24%

of azaspirocyclohexadienol 433 and demethylated aza- (b)

DMF, 80 °C O

Ph Me

under O (1 atm) spirodienone 410 in 42 and 6% yield, respectively, with- 2

out the formation of expected spirocyclohexa-2,4-dienone 432

+ N

434 NMe (Scheme 35, part b). NMe

Ph Ph

Based on these results, a mechanistic pathway was pro- O

410 6% 0% posed, as depicted in Scheme 36. In this mechanism, the 434 denitrogenative formation of iminylcopper II via deproto- Scheme 35

42 S. Chiba ACCOUNT

2 N

N Ph

2 R

2 R R N

R base

[Cu(OAc) for initiation]

O [Cu ]

[Cu –OH]

II VI N [Cu ]

N Ph

R N

R R

O I

base

, H •base N 2

O O

III

[Cu ] [Cu ]

2 R

O R

N R

III

[Cu ]

1 R

O N

2 IV

2 R R

O III

Scheme 36 respectively, affording IV. The subsequent isomerization Zimmermann, V. Angew. Chem. Int. Ed. 2005, 44, 5188. of IV to give peroxydiene V followed by elimination of (c) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297. hydroxidocopper(II) species VI72 would form the aza- (d) L’abbe, G. Chem. Rev. 1969, 69, 345. (e) Boyer, J. H.; Canter, F. C. Chem. Rev. 1954, 54, 1. (f) Smith, P. A. S. spirodienone. The observed transfer of the phenyl group Org. React. 1946, 3, 337. shown in Scheme 35, part a, might proceed via carbon– (4) For safety issues on the handling of organic azides, see: nitrogen bond cleavage of IV. Keicher, T.; Löbbecke, S. In Organic Azides: Syntheses and Applications; Bräse, S.; Banert, K., Eds.; John Wiley & Sons: Chichester, 2010, 3. 5 Conclusion (5) (a) Medal, M.; Tornoe, C. W. Chem. Rev. 2008, 108, 2952. (b) Schilling, C.; Jung, N.; Bräse, S. In Organic Azides: Syntheses and Applications; Bräse, S.; Banert, K., Eds.; John We have explored the intriguing chemical reactivities of Wiley & Sons: Chichester, 2010, 269. several organic azides, such as vinyl azides, cyclic 2-azido (6) For reviews, see: (a) Katsuki, T. Chem. Lett. 2005, 34, alcohols, and a-azido carbonyl compounds, which can 1304. (b) Driver, T. G. Org. Biomol. Chem. 2010, 8, 3831. lead to various kinds of synthetic transformations to give (7) (a) Trost, B. M. Angew. Chem. Int. Ed. Engl. 1995, 34, 259. nitrogen-containing molecules. Although there is a gener- (b) Trost, B. M. Science (Washington, DC, U.S.) 1991, 254, al conception that ‘organic azides = 1,3-dipolar cyclo- 1471. addition (click chemistry)’, organic azides potentially (8) (a) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40. (b) Wender, P. A.; Croatt, M. possess diverse chemical reactivities working as a one- P.; Witulski, B. Tetrahedron 2006, 62, 7505. Downloaded by: University of Oxford. Copyrighted material. nitrogen unit which can be driven by the elimination of (9) (a) Timén, Å. S.; Risberg, E.; Somfai, P. Tetrahedron Lett. molecular nitrogen. 2003, 44, 5339. (b) Söderberg, B. C. G. Curr. Org. Chem. 2000, 4, 727. (c) Knittel, D. Synthesis 1985, 186. (10) For prior studies on iminyl radical formation from vinyl Acknowledgment azides, see: (a) Montevecchi, P. C.; Navacchia, M. L.; Our co-workers whose names appear in the references are gratefully Spagnolo, P. J. Org. Chem. 1997, 62, 5864. (b) Bamford, acknowledged for their intellectual and experimental contributions. A. F.; Cook, M. D.; Roberts, B. P. Tetrahedron Lett. 1983, The work was supported by funding from Nanyang Technological 24, 3779. University, Singapore Ministry of Education (Academic Research (11) For our previous report on rhodium(II)-catalyzed indole Fund Tier 2: MOE2010-T2-1-009), and the Science and Engineer- formation from 2-aryl-2H-azirines, see: Chiba, S.; Hattori, ing Research Council (A*STAR grant No. 082 101 0019). G.; Narasaka, K. Chem. Lett. 2007, 36, 52. (12) Alves, M. J.; Gilchrist, T. L.; Sousa, J. H. J. Chem. Soc., Perkin Trans. 1 1999, 1305. References (13) (a) Alves, M. J.; Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.; Gilchrist, T. L. Tetrahedron Lett. 2000, 41, 4991. (1) Griess, P. Proc. R. Soc. London 1864, 13, 375. (b) Carlson, R. M.; Lee, S. Y. Tetrahedron Lett. 1969, 10, (2) Curtius, T. Ber. Dtsch. Chem. Ges. 1890, 23, 3023. 4001. (c) Leonard, N. J.; Zwanenburg, B. J. Am. Chem. Soc. (3) For reviews, see: (a) Lang, S.; Murphy, J. A. Chem. Soc. 1967, 89, 4456. Rev. 2006, 35, 146. (b) Bräse, S.; Gil, C.; Knepper, K.;

Synlett 2012, 23, 21–44 © Thieme Stuttgart · New York ACCOUNT Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules 43

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