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6.7 Five-membered ring compounds with two or more heteroatoms 6.7.1 Introduction NabzXNabYXNabzXNabzCH

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6.7 Five-membered ring compounds with two or more heteroatoms 6.7.1 Introduction

a N

b z X

a N b

Y

X a N

b z X

a N

b z CH2 a N

b z CH2 a N

b z CH3

z Y-

Azoles reactions involving negatively charged intermediates.

pKa values of some azoles and azoliums.

N H

N S

H

N O

H

O N S N H

H N N H

N N N H

N N N H

N N

N N H

N N H

H

N N H

H

H N N H H

N N N H

H

N N

N N H H

N N H

N N H

H

N O

H O

N H 16.5

14.52 10 9.4 4.8 13.2

7.00 2.53 0.8

5.5

2.5 -0.51 -2.97 -4.7

-2.20

2.2 1.2 -3.0

(2)

N N H

R

N N H R

N N H R N

N H R

N N R

H

N N

R H

3

5

5 4

Tautomerism in pyrazoles and imidazoles.

N N O2N

H

N N O2N H

Preference for the 4-nitro structure in 4(5)-nitroimidazole.

6.7.2 Imidazoles

6.7.2.1 Introduction

N N

N N

N N H

H N

N H

N N H

H H+

H-

H+ H- pKa = 14.5 pKa = 7.0

N N H H2N

HO2C H

N O2N N Me

OH

N N OH

Cl

Bu

N N N

N H

N N

Ph Ph

N N

Cl Ph

Ph 1

2

3

4 5

(3)

6.7.2.2 Ring Synthesis

R1 O

R2 OH R2 OH

R1

NHCHO OH

R2 O R1 NHCHO

R2 OH NHCHO NHCHO R1

N N R1

R2

H

+ HCONH2 HCONH2

R1 O NH R2

N N R1 R2

H

NH2 N

N R1 R2

H

SH KCNS

H2NCN

N CN OMe Me

N CN NHCH2X Me

N N H2N

Me X

H + H3NCH2XCl NaOEt

(X = CN or CO2Et )

NH MeO

NH CHCl2 N

H OMe MeO OMe

MeO NH2

N N H CHCl2 CHO

HCO2H

(4)

N O

R1 O- R2

OMe

O

NTs R3

N H

NHR1 O

N N

O

H2NOC

R2 R1

N H N

R3 R1 R2

1) TFA, H2O 2) HOAc, 100 oC

1) R2NCO, NEt3 2) TFA, H2O

48

45 46

47

TL, 1998, 1477.

H Ar N O

N3

N N

CHO Cl

N POCl3 Ar

DMF

49 50

JOC. 1998, 7136.

Cl N Cl

NC R1 OR2 O

HN NH

S

S

CO2R2 R1

51 52

(NH4)2S

Synthesis, 1998, 1437.

N R1

XMen NAr Ph

N N Ar CH2l2 Ph

Zn / Cu

R1

53, X = S, N 54

TL, 1998, 4785.

N N

N N Boc

Boc

Boc

Boc E 1) sBuLi

2) E+

60 61

TL, 1998, 4255.

(5)

6.7.2.3 Reactions N N H

N N+ H

R X O-

N+ N H

R O- X

N N

O+H2 O- R H

N N H

N N

R O + RCOX

- X- H2O

H+ - H+ O H

R N+ N

6

Hydrolysis of N-acylimidazole, 6, and nucleophilic catalysis by imidazole of hydrolysis of RCOX.

N N H Ph

N+R N COPh Ph

N N R Ph

N N COPh Ph

N N

Ph R

BF4 -

RX, NaOMe

(major) (monor) PhCOCl, NaOH

R3O+BF4 -

Na2CO3aq.

Selective alkylation of 4-phenylimidazole

(6)

N N H

N+ N H

H E

N N H

H E

N N

H E H N

N H H

E

N N H

E H N

N H

E H

Electrophilic attack at C-2 and C-5 of imidazole

N N

R

R

N N COPh

H

N N COPh

H

N N H

COPh

7 8

N N Me

Br

N N Me

NC5H10

N N Me

NH2 Me

O2N

N N Me O2N

Cl

N N Me O2N NC N

N Me Me

O2N Br N H

+ NH3

+ NaCN

200oC

75oC

100oC

The nucleophilic displacement in imidazoles 6.7.3 Pyrazoles, triazoles and tetrazoles

6.7.3.1 Introduction

N N Ph

Me Me Ph

N N

N

OH CMe3

Cl

9 10

MeSO4-

(7)

N N Ph

Ph

Bu O

O

N N

N

N OH

F

F

N N

11 12

6.7.3.2 Ring synthesis

MeCOCH2COMe + H2NNH2 OH-

R1COCHR2Cl + XCNHNH2

S

MeCOCH2CMe

NNH2 N N

Me

Me H

N N R2 X

R1 H N N

S X

R1 R2

H

H+

Routes to pyrazoles

N N N

Ph Ph

H N

N N Ph Ph

NH2 N

N Ph

Ph O

H

OHN N H

Ph Ph

PhCONHNH2 + PhCSNH2

PhNHNH2 + PhCONHCHO

Routes to 1,2,4-triazoles

NH2NHR1

R OEt

N NHCHO N N

N NHR1 109

110, R1 = H 111, R1 = CO2Et 112, R1 = CO2tBu R

J. Heterocyclic Chem. 1998, 377

(8)

SMe SK

NC H2O

N N N H

SH H2N

113

114 H2NNH2

J. Heterocyclic Chem. 1998, 827.

Ph3P+

-O Ph N

N Ph3P+ N

-O

Ph Ph

N N N Ph

Ph

N N N R

Ph NNHPh

NNHPh R

H

R N

H N

NPh NPh

N N N Ph R

NPh + PhN3

Routes to 1,2,3-triazoles

(EtO)2P N3 R1

O

Ph3P O

R2

(EtO)2P R1

N N N R2

O 88

86 87

Synth. Commun. 1998, 1215.

O

Me SnMe Sn

N3 Me

OSiMe3 Me

N N

N N

Ar Sn O

SiMe3

Me Me

N N

N N Ar

H N

N N N R2 R1

N N

N N

R1 R2

NNHR2 N2+

R1

N R2 N3 R1

NNHR2 NH2 R1

N R2 OTf R1 O

R1 N R2 H

+ HONO

Me3SiN3 ArCN H2O

Tf2O NaN3

Routes to tetrazoles

(9)

TMSN3 + R1CHO + R2NH2 + CN CO2R3 Me2N

MeOH H3O+

N N N NN R2

R1

CO2R3 rt

120

121 TL, 1998, 2735.

6.7.3.3 Reactions

N N NO2

N N NO2

H

N N H O2N

Rearrangement of 1-nitropyrazole in sulfuric acid

N N Me

CO2Me

Me N N

H Me

CO2Me

CO2Me

Me N Me

N

CH2N2 MeI

N N N SiMe3

N

N N R R

X

+ Me3SiX

N N N Me

N N N Me

Me N

N N Me

Me Me

BF4-

2BF4-

Alkylation of pyrazoles and triazoles

N N

N N Br

Me

N N

N N Me Br

Y

N N

N N Br

Y Me

N N

N N Y

Me Y-

(10)

N N

N N Ne

Br N N

N N Me Y

N N

N N Cl

Ph

N N

N N ArO

Ph

N N

N N Ph O

H Y-

+ ArO- H2/Pd

ArH + Y

Br N Me

N N N

Nucleophilic displacement reactions of 5-halotetrazoles

N N N

NHBoc

BuLi

N N N

NBoc

N N N

NHBoc E

TMEDA

E+

101 102 103

JCS P1, 1998, 2301.

O S Tol N

N NMe O

O

N

N NMe O

Me O HO

P(OMe)3

115

116

117 TL, 1998, 1405.

6.7.3.4 Ring cleavage

N N

N N R1 R2

N N N R2

R3

R1

NR1 R2

R3

N2 N3 R2 NR1

Ring-chain tautomerism in tetrazoles and in 1,2,3-triazoles

(11)

N N N R

H2N

Ph

N N N R

N Ph

H H

N2 H2N N

R

Ph

N2 N NH

Ph H

R

The Dimroth rearrangement N

N

N N Ph Ph

N N

Ph

N N

Ph H 28 hv

-N2

Photolysis of 1,5-disubstituted tetrazoles

N N N R1 R3

R2

R2

R3 NR1

R2

R3

NR1 N

N N R3 R2

R1

30

Pr oduc t s

NR1 R2

R3

Decomposition of 1,2,3-triazole

N N

N N N2+

H

N N

N N N2

Cl- C + 3N3

Decomposition of tetrazole-5-diazonium chloride

N N Me

Me

N N Me

Me

32 33

hv

Photochemical rearrangement of 1,3-dimethylpyrazole

(12)

N N

N N Li

Me

MeNCN + N2 Li

34

Cleavage of 5-litho-1-methyltetrazole

CO2Me

N N

CO2Me CO2Me

N Me N

Me

Me Me Me

Me

hv pent ane

145oC CH2N2

CH2N2

Formation and decomposition of 4,5-dihydro-3H-pyrazoles 6.7.3.5 Azoles as ortho-directing groups for metallation

N N

Me N N

Me

Li

N N Me

CO2H

N N

N N

CPh3

N N

N N

CPh3

Li

N N

N N

CPh3

B(OH)2 BuLi,

-70oC

1. CO2 2. H3O+

BuLi

<-20oC

1. B(OPri)3 2. NH4Cl

Azoles as substituents for directed lithiation 6.7.4 Benzodiazoles and benzotriazoles

N N MeO

H

S N

O

Me Me OMe

N N

Me N

N Me

H O

35 36

(13)

N N N

OH

N N N

Cl

N N N

X (X = OR, NR2, CN, N3, etc.)

SOCl2 X-

N N N

N

N H

N Pyrrole, AlCl3

1-Alkyl-substituted benzotriazoles as reagents

N R

R N

N N

Me N

N N

R

J 8.65

J 6.79 7.33

37 38 7.8339

NH2

NH2

NHCOR

NH2

N N H + RCOX R

40 Synthesis of benzimidazoles from benzene-1,2-diamine

N N N

NH2 N

N N

NH2

N N N

N N

N N

N Pb(OAc)4

Pb(OAc)4

+ 2N2

+ N2 CN

CN

Oxidative fragmentation of 1- and 2-aminobenzotriazole N

N

N N

Y

X X

Y

N H X Y

heat or hv

(14)

The Graebe-Ullmann carbazole synthesis 6.7.5 Oxazoles and thiazoles and their benzo derivatives 6.7.5.1 Introduction

S O

O

H N

O

N O

OH O H

41 OH

O O

N H

OH

O OMe

N O

O N

N O OMe

O OMe Me

O

42

N

S N

N Me

HOCH2CH2

NH2

Me H

N

S S

N HO

CO2H H

43 44

6.7.5.2 Ring synthesis

EtO2CCHMeNH2

4-MeC6H4COCH2NH2

HCO2COMe P2O5

HCO2H P2S5

O O N EtO

Me H

H

O O N

H H Ar

N Ar S

N EtO O

Me

Oxazole and thiazole synthesis

(15)

N S Ph Ph

N R2 O

R1 PhCOCH2Br + PhCSNH2

R1COCHXR2 + HCONH2

S

NH2Br- O

Ph

Ph

O

NH2X- O

R2 R1

Synthesis of thiazoles and oxazoles from α-haloketones

S R1 N

H

CO2Et

N2 EtO2C CHO

R1 SMe

N CO2Et

R2 Cl O

R2 OEt S

N O EtO2C

R2 R1

N S R1 R2

EtO2C

N

O R

EtO2C + RCN Rh(II) cat.

Me3O+BF4-

Methods of synthesis of oxazole- and thiazole-4-carboxylic esters 6.7.5.3 Chemical properties

N X R2 R3

R1

N S Me

HOCH2CH2

R

N S Me

HOCH2CH2

R

45 46

N

O CHO

N

O Li OLi

NC

OSiMe3

Me2NCHO Me3SiCl NC

Reversible ring opening of 2-oxazolyllithium

N O Cl Ph

Ph

N

O NHPh Ph

Ph + PhNH2 145oC

(16)

N S Br

N S NO2

N S SPh

N S Me

N S Me

NH2 N

S OMe + PhSH 50oC

+ MeO-

+ NaNH2 150oC

Nucleophilic substitution in oxazoles and thiazoles

N O Me

EtO N

CO2Et EtO2C OEt

Me O

N CH2OH

OH

Me HOCH2

N

OH

Me CO2Et EtO2C

N

OEt

Me CO2Et EtO2C

O

CO2Et EtO2C

H

H+ 110oC

LiAlH4

Synthesis of pyridoxol by Diels-Alder addition N

O N

CN CH2 CHCN O

N CN TEA, 80oC

MeO2CC CCO2Me

N

OEt CO2Me MeO2C

O N

Et O O

20oC

O

MeO2C CO2Me

OEt

+ HCN

N O

O

Me

Me Me N

Me O

O

Me O

O Me

+ HCN 136oC

(17)

Oxazoles as dienes

N O R1 R3

R2

O O N O R2

R3 R1 O

N O O R2

R3

R1

N R3

R1 R2

O

O O

1O2

The addition of singlet oxygen to oxazoles

N N Ph Me

O N

Me Ph

N O Me Ph

N CHO Me

Ph

N O Ph Me

O N

Ph Me

Photorearrangement of 4-methyl-2-phenyloxazole

N

O R

Y X

O

X Y

O O

N CR N

O R

X Y

O heat

The Cornforth rearrangement ( X = H, Cl, NR2; Y = Cl, OR, O-)

N O Me Me

R1

N O Me

Me R2

R1

N

S R

N

S R

Me

N S

Me

R R2

R1 OEt

O

R H

O TfO-

MeOSO2CF3 NaBH4

H+, EtOH 1. BuLi

2. R2I

4,5-Dihydrooxazoles and thiazoles as protecting groups.

(18)

6.7.6 Isoxazoles, isothiazoles, and their benzo derivatives 6.7.6.1 Introduction

O N O-

H3NCH2 N O N

O- H

H

O N H3N O-

O N H

Cl H3N

-O2C H

49 50 51

52

N

X X

N

53 54

6.7.6.2 Ring synthesis

C CHOEt EtO2C

PhOC O N

EtO2C

Ph + NH2OH

O N Ph

+ NH2OH PhC CCHO

O N R3

R2 R1

HO N

R2 R1

N R2

-O R1

2 BuLi 1. R3CO2Me 2. conc. H2SO4 Isoxazoles by cyclization reactions

HC CCHO H2NNSO3K+ HC CCH NSSO3K+ A route to isothiazole

S H2N

NH Me

I S H2N

NH Me

S N H2N

Me I2

(19)

CN CN HO2C

Na+S-

Me S Cl

CN C

N S N

NH2 NC

NH3 Me NH2Cl

O N Ph HO2C

Me S N

Me

HO2C Ph Ph

NH2 HO2C

Me O

H2/Ni 1. P2S5

2 chloranil

Isothiazole synthesis by formation of the N-S bond.

X R

N

OH N

O R

base ( X = Cl, Br, NO2)

NO2 R

O O

N reducing R

agent

O2N

N S O2N R

R O SBr

NH3

N S CH2NH2

SH

I2

Routes to benzisoxazoles and benzisothiazoles

N N2 R

O O

N R

+ N2

2,1-Benzisoxazoles from 2-azidozryl ketones

(20)

6.7.6.3 Chemical properties

O N R1 R2

R3 R3 NH2

R1 R2

O

R3

R2 R1

O metal-ammonia

reduction

O N R1

R2

R1 CN R2 O-

O N

Ph Ph

PhC CO- + PhCN

Cleavage of isoxazoles

O N

O N Me

Me

O

NH2

H2N O Me Me

O N

H2N Me Me

H2/Ni Et3N

Reductive cleavage of isoxazoles in corrin synthesis.

O N R2 H

R1 R3

:B

R2 R3

O-

NR1

R3 R2

O

C NR1

O N

H

R

C O

NR N

R :B O

Anionic cleavage of isoxazolium

N Y X

O U

V

W N WV

U O X

Y

(21)

Rearrangement of isoxazoles and related heterocycles

O N Me

N

H NHPh

S N

N S Me

NHPh O

57 58

6.7.7 Oxadiazoles, thiadizoles and related systems 6.7.7.1 Introduction

N N

X N X N

N X N N

X N

1,2,3- 1,2,4- 1,2,5- 1,3,4-

Isomeric oxadiazoles and thiadiazoles

N O N R1

R2

N N

S N R

N N S N MeO2C

O

Ar R

R1 R2 O

N2

59 60 61 62

N S N

N OCH2CHOHCH2NHCMe3 O

N N

MeCON S SO2NH2 H

N S N EtO

CCl3

N S N N2

+

Ph

63 64 65 66

6.7.7.2 Ring synthesis

O O N H2N

R2

R1 N

O N R1 R2

heat

(22)

N O N R1 R2

R1 R2

HON NOH

heat

N R1

R2CH2 N H OEt O

N S N R1

R2 SOCl2

NH2Cl-

H2N R N

S N Cl

R Cl3CSCl

R

H2N NH2 O

N S N

R OH

S2Cl2

Some general methods for preparing oxadiazoles and thiadiazoles.

6.7.7.3 Chemical properties

N S N Cl

Ph

N S N Cl

Y

Ph

N S N Y

Ph N

S N- Cl

Y

Ph

Y- -Cl-

Nucleophilic displacement of chloride in 5-chloro-3-phenyl-1,2,4-thiadiazole N

N

PhCO S Cl N

S N

Cl N N

Ph O SO2Me

N O N Cl

Me

67 68 69 70

N S N H3C

CH3

N S N LiCH2

CH3

N S N HO2CCH2

CH3 BuLi

N S N

CH2PPh3Cl-

S N N

CHPPh3 NaOH aq

Acidity of α-hydrogen atoms

(23)

ArCN + NCO MeS-

N O N H

R

N O N HO- H

NCCH NO-

N O N

H Ph

Et HO-

EtN C

Ph NO

N N

S Ph

EtO- H PhCN -SCN

N S N Ar

HO- H

ArC CS- N2 +

Examples of anionic cleavage

N N

Me O Me

N N Me N

R

Me N N

Me H

NHR Me O

+ H2O RNH2

Ring opening of 2,5-dimethyl-1,3,4-xoadiazole and recyclization

N O N

Ph N

NHAr

Ph N

N N N

Ph H

Ph

Ar O

76 An example of ring interconversion.

(24)

N O N R2 R1

-O

R2 NO R1

ON N

O N O- R2 R1

R1C N O- + R2C N O-

Thermal reactions of 1,2,5-oxadiazole 2-oxides

N S N R1

R2

N Se N R1

R2

R1 R2 S

C R1 R2

S

R1C CR2 + N2 + Se heat

heat

Thermolysis of 1,2,3-thiadiazoles and 1,2,3-selenadiazoles

6.7.8 Betaines and mesoionic compounds Betaine: dipolar structure

Mesoionic compounds: cannot satisfactorily be represented by a single covalent or dipolar structure.

N N N R

R

Me

O-

N N N R

R

Me

O- a.

N N Me R R

R O-

N N R R

R O-

Me b.

(25)

N N N

-O

Me

Me

N N N

-O

Me

Me

N N N O

Me

Me

N N Me MeSO2N

Me Me

Me

N N Me MeSO2N

Me Me

Me

N N Me MeSO2N

Me Me

Me c.

d.

Betains and mesoionic azoles 6.7.8.1 N-Oxides and N-imides

NO2 NCHO Me

NHOH NCHO Me

N+ N

O-

Me

N N

O

CO2Me Me

N N

Me

CHCO2Me CHO NaBH4/Pd

HC CCO2Me

Formation and dipolar cycloaddition of 1-methylbenzimidazole 3-oxide

N S

N S

NH2

N S

NCO2Et

N S

N CO2Et

CO2Me

CO2Me

Me

SO2ONH2 Me

Me

-OSO2Ar

79 79

ClCO2Et, K2CO3

MeO2CC CCO2Me

N-Amination of thiazole and generation of thiazolium N-imide

(26)

N N

O OH

PH O

N N

O O Ph

Me O

O

O N

Ph N O

(MeCO)2O heat

Formation of N-phenylsynone

Examples of 1,3-dipolar addition of mesoionic heterocycles

N

O O

Me Ph

Ar

ON Me

Ar Ph

MeO2C MeO2C

O (E)- MeO2CCH CHCO2Me , 80oC

Mesoi oni c c ompound Di pol ar phi l e Pr oduc t

O

N O

Ph Me

Ph

N Ph

Ph

Me HC CH , 120-130oC

N

S O

Ph Ph

MeO2CC CCO2Me , 80oC

N O

Ph CO2Me MeO2C

Ph

, 140oC O

N

N O

PhCH2N

N N Ph

CH2Ph PhCH CH2

N N

N O

Me

Me EtO2CN NCO2Et N N N

N

Me

EtO2C O

EtO2C ,140oC Me

N O O

Ph

N O O

Ph H

O

MeO2C CO2Me

Ph

+ HNCO

Tautomerization of 2-phenyloxazol-4-one

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