tetrazole and triazole

Shrikant G. Pharande

Tetrazoles and TriazolesSynthesis and applications

NN N

N

R

R11

23

45

NN N

NH

R

1

2

3

45

1, 5 di-substituted tetrazole

5 -substituted tetrazole

Tetrazoles

1.Introduction- five-membered, doubly unsaturated ring consisting of one carbon and four nitrogen atoms

NN

NH

N

1.Introduction- five-membered, doubly unsaturated ring consisting of one carbon and four nitrogen atoms

- they are unknown to nature

1.Introduction- five-membered, doubly unsaturated ring consisting of one carbon and four nitrogen atoms

- they are unknown to nature- divided in three types

parent monosubstituted disubstitutedN

NNH

N NN

N

N

R

NN

N

N

R

NN

NH

N

R1 2 5

NN

N

N

R

NN

N

N

R1

2 5R1 R15

1.Introduction- five-membered, doubly unsaturated ring consisting of one carbon and four nitrogen atoms

- they are unknown to nature- divided in three types

- exist in the tautomeric formsN

NNH

N NHN

N

N

Mol Divers. 2015,19(1):189-212

1.Introduction- tetrazoles are stable to various chemical reagents such as oxidants, acids, bases, alkylating agents, dienophiles, etc.

1.Introduction- tetrazoles are stable to various chemical reagents such as oxidants, acids, bases, alkylating agents, dienophiles, etc.

- thermal stability is high

1.Introduction- tetrazoles are stable to various chemical reagents such as oxidants, acids, bases, alkylating agents, dienophiles, etc.

- thermal stability is high

- tetrazoles are medicinally important

Mol Divers. 2015,19(1):189-212

NNH2

HNO2

NH

NC NN

NN

NC

- H2O

HON

O-H2O

NNH

NC

NH N O

NN

NN

NC

OH

-H2O

H

Chemical Reviews ,41,1,1947

First synthesized tetrazole by J. A. Bladin in 1885

2. Synthesis

2. SynthesisUnsubstituted tetrazole

Z. Anorg. Allg. Chem. 2008, 17111723

NN

NH

NHCN HN3

sealed tube, 100oC

80%

NaCN NaN3AcOH, 120oC

42%

NaN3 NH4ClHC(OEt)3AcOH, 80oC

60%

2. Synthesis

NN

NH

N

R CNNaN3, NH4Cl

MW, 10- 25 minDMF

R CNAl(N3)3

THF, 80oC

R CN(CH3)3Al

TMSN3, Toluene80oC

R CN

ZnCl2 / ZnBr2/ I2

NaN3, H2O100oC

R CN

R1SnN3, H+

R

R

N

NH

NH2

CN

1. N2O4 orPPh3, TMSN3

DEAD

2. H+ / HO-

orTMSN3,TBAF

R NH2

O1. NaN3,SiCl4

2. H2O

N NN

N

PMB

1. nBuLi, - 98oC

R1

O

NO

2.

3. TFA

R = alkyl or arylEur. J. Org. Chem., 2012, 31, 6101.

5- sub. tetrazoles

2. Synthesis

NN

NH

N

R

N

NN

N

R

R1

1. DBU, DCM

2. TFA / H2O 90%BMCL.,2002,12,1579.

CAN

CH3CN, H2O,65%

TL.,1998,39,3367.

H2, (50 psi) PdCl2

85%

Tetrahedron,2011,67,8902.

HCO2NH4

Pd/C 10 %

Tetrahedron,2011,67,8902.

98%

BF3-Et2O

(HSCH2CO2CH2)4CCH3CN

93%

JOC.1999,64,9301.

HCO2K

Pd/C 20 %

TFA, anisole

98%

60oC60%

JOC.1999,64,9301.

BMC.2007,15,7087.

N

NN

N

R

R1

R1 = 1= CH2-CH2-CN 5=6= (CH3)2C-Ph 2=7= PMB 3=4 = Bn, PNB

1

2

3

4

5

6

7

5- sub. tetrazoles by deprotection

2. Synthesis1, 5- sub. tetrazoles

RN3 CN

O120oC

sealed tube24 hrs

NN N

NR

O

R = Bn 73% PNB 54%

By using Ugi-azideR

NH2 R1-CHO

TMSN3R2-NC

MeOH

RT

N

NN

NR2

HN

R1

R

R, R1, R2 = alkyl or aryl 71-96%18 examples

Tetrahedron 67 (2011) 8902-8909J. Mex. Chem. Soc. 2013, 57(4)

2. Synthesis

RNH2 R1-CHO

TMSN3R2-NC

MeOH

RT

N

NN

NR2

HN

R1

R

R, R1, R2 = alkyl or aryl

One pot ugi-azide reaction

J. Mex. Chem. Soc. 2013, 57(4)

RNH2

R1-CHOR

N R1

TMSN3 MeOH

H N N N

TMSOMe

RNH

R1N R2

RHN R1

NR2

N N N

RHN R1

NNR2

NN

RHN R1

NN N

NR2

Ugi-azide reaction mechanism

J. Mex. Chem. Soc. 2013, 57(4)

Ugi-azide reaction literature survey

R1NH2

R2-NC

OO

O

1. TMSN3, MeOH

2. TFA 10%, DCE

N

O

NN N

NR2

R1

40-78%

Org. Biomol. Chem., 2013, 11, 6036.

O

O

OR N

O

R1

NN N

NR2

R

29-66%8 examples

SN

OR1

N NN

N

R2

NN

OR1

N NN

N

R2

SO

O

22-96%5 ex.

58-93%6 ex.

N NN

O

R1

N NN

N

R2

51-78%5 ex.

O

R1

R2NH2

R3NC

TMSN3

MeOH

RT

R1

NH

NNN

NR3

R2 AgNO3 10 mol%

CH3CN, 80oCN

NNN

NR3

R2

R1

40-93%26 ex.

One pot ugi-azide/cyclisation

EUR. J. ORG. CHEM.,16, 2014, 3379–3386

Enantioselective Passerini-Type ReactionR1-CHO

R2-NC

HN3

Cat.

toluene, - 40oC N NN

N

R1

OH R2 45-99%

21 examplesee 97%

Angew. Chem. Int. Ed. 2008, 47, 9454 –9457

N

R-NC

HN3

NH

NN N

N R

Cat.

L.AlClHN3

HCl

L.AlN3

NAlL.N3

N

NR

AlL.N3

HN3

NH

NN N

N R

Enantioselective isoquinoline-tetrazole by ugi-azide

3. Reactivity5- sub. Tetrazoles - alkylation

HN

NN

N

MePh3CCl

aq. NaOH

(C4H9)4NBr

N

NN

N

MeCPh3

75%

NNN

HNBr

Br

Et3N

MW

NNN

N

Br

NNN

N

Br

1:1

72%

NN

NHN

O S

SToluene

NN

NN

reflux

97%

Eur. J. Org. Chem., 2012, 31, 6101.

3. Reactivity5- sub. Tetrazoles - arylation

FNO2

NO2

HN

NN

N

R

Et3N

acetone,RT

NO2

NO2

NN

NN

R96-99%

R = Ph, 4MeOPh, 4MePh, 4ClPh, 4NO2Ph

F

NO2

HN

NN

N

R

NaOH, DMSO

MW, 90oC

NO2

N

N NNR

NO2

NN

NN

R2:374%

R = Me, Ph, 4MeOPh, 4MePh, 4ClPh, 4ClC6H4CH2

Eur. J. Org. Chem., 2012, 31, 6101.

4. ApplicationsMedicinal chemistry

F

F

NNN

N N

ON N

NN

TAK-456

1 sub. tetrazole

N N

NN

NN

Bu

ClOH

K

Losartan potassium

5 sub. tetrazole

antifungal

antihypertensive

NH

C7F15

ON N

N

HN

prefluoroamidesantidiabetic

NH

H

H

HNN

NNH OH

O

NN

NNH

ON

OH

H2N

OHO

AMPA and glutamate receptors

Chemistry of Heterocyclic Compounds, Vol. 43, No. 1, 2007

4. ApplicationsMedicinal chemistry

N

S

NN N

NR

O

anti inflammatory

1, 5 disub. tetrazoles

R= Me, Et, Ph, 4ClPh 4NO2Ph 2NO2Ph 4OHPh 4NH2Ph

Et

NH

NH

O

N

F / Cl

N NN

NMe

anti inflammatory

phenothiozine derivetives

N-alkylaryl-piperdineurea derivetives

N

NNN S

O

OO

NO

HN O

S

NN N

N5-thiotetrazoles

anti ulcer

HO

OHO

NH

O NO

O

OHO

S NN

NN

OMeH

Latamoxef

anti-biotic

Chemistry of Heterocyclic Compounds, Vol. 43, No. 1, 2007

4. Applicationsagrochemistry

NH

H / ClO

N

ON N

NN

R NH

H / ClO

N

ON N

NN

R

R = Me, Et, propyl, t-butyl, cy-hex, octyl, Bn.

tetrazole urea

Herbicidal property

NN N

N

N N

SNH

OO

NH

O

N

N

OMe

OMe

NN N

N

N N

SNH2

OO

Azimsulfuron

Herbicidal

MPS

J. Agric. Food Chem. 1989, 37, 196-200J. Agric. Food Chem. 2004, 52, 8081-8085

4. ApplicationsOther applications – in fluorescent

N

NNN

NO

O

ZnN

NN N

N O

O

H2O

H2O

Zinc complexes of pyridyl-tetrazole

Highly fluorescent

Inorganica Chimica Acta 432 (2015) 50

ON

N NN

HN

Al

O3N OHH2O

OSMD

fluorescence “turn-on” sensor

Dalton Trans., 2014, 43, 6429–6435

4. ApplicationsOther applications

- components of various combustible and thermally decomposing systems including solid propellants, blowing agents and initiating explosives.

-selective recovering of palladium from the industrial wastes

1,2,3 triazoles

NH

NN

1

2

34

5

1.Introductionfive-membered ring of two carbon atoms and three nitrogen atoms

Divided in three main groups

Monocyclic1,2,3 triazole

benzotriazole 1,2,3 triazolium salt

NH

NN

R

R1

NNH

N

R

R1

NN

N

R

R1

1H-1,2,3 triazole 2H-1,2,3 triazole

4H-1,2,3 triazole

NH

NN

NNH

N

1H-benzotriazole

2H-benzotriazole

NH

NHN

R

R1

NH

NNH

R

R1

1,2,3 triazolium salt

NH

N

HN

NH

NHN

benzotriazoliumsalt

1.Introduction

NN

N

R1

RMedicinal chemistry

Agrochemicals

Fluorescent materials

dyes

Polymer chemistry

Chem. Rev. 2008, 108, 2952–3015

2. Synthesis

R R1-N3N

NN

NN

NR

R1

R

R1

1,4 sub. 1,5 sub.

DMF/DMSO/Toluene

MeOH/EtOHheating

1. Without using catalyst

2. By using catalyst

R R1-N3N

NN

R

R1

1,4 sub.

cat.

solvent, RTor

MW

Chem. Rev. 2008, 108, 2952–3015

2. SynthesisR1 R2-N3

NN

NR1

R2

DMF, RT

Cu(I)

HR'

H+

CuLxR'

N N NR2

CuLxR'

N N NR2

CuLx

N N N

R1

R2

N NN

R CuLx

H+

N NN

R H

R2

R2

[CuLx]

RDS J. Am. Chem. Soc, 2005, 127, 210-216.Organometallics 2007, 26, 4389-4391.

Mechanism

2. SynthesisUgi- triazoles – linked triazole

99-100%20 examples

O

ClOH

O

H2NCN

DCM

ClN

ONH

O 1.NaN3

2. CuSO4.5 H2Osod. ascorbate

R

NN

ONH

ON

N

R

R1

R2R1

R2R2

R1

O O

O

O

R =

Bioorg. Med. Chem. Lett. 22 (2012) 2598–2603

R2 = n-butyl, 2-F, 4- Cl, BnR1 = 2-Br, 2-Cl, 2-F, 4-F

2. SynthesisUgi- triazoles – 6 component ugi

ACS Comb. Sci. 2014, 16, 176−18317 examples

81-92%

2. SynthesisUgi- triazoles – peptoid mimics

Org. Biomol. Chem., 2011, 9, 5024–5027

2. SynthesisUgi- triazoles – fused triazole

Tetrahedron Lett. 2004, 45, 8439

86-98%7 examples

2. SynthesisUgi- triazoles – fused triazole

BocHN COOH

N3

R2CHO

R1NCBocHN

N3

O

N

R2

NH

OR1

70oC, 36 hrs

BocHN N

N

O R2NH

O

R1

NN

NH2

MeOH

RT

R1= t-But, Bn, cyclohexylR2= Me, Ph, 4-BrPh, 3-indolyl, cyclohexyl, piperonyl

39-94%13 examplesOrg. Biomol. Chem., 2014, 12, 6986–6989

2. SynthesisUgi- triazoles – macrocycles in pot

Oxazole intermediate

Org. Lett., 2006, 8, 4145

2. SynthesisUgi- triazoles – click and post condensation

Eur. J. Org. Chem.,2013, 1223One example by using terminal alkyne

3. ReactivityAlkyl nucleophilic sub. reaction

NNHN

NO2

Cl

K2CO3

acetone

NN

NNO2 N

NN

NO2

1:1.7

Farmaco 60 (2005) 367–375

Pd catalysed arylation at c5

NN

NR1

R2

Ar-BrN

NNR1

R2Ar5mol% PdBu4NOAc

0.5M NMP, 100oC

Org. Lett., 9, 2007, 2333

4. ApplicationsMedicinal chemistry

NH

HNCl

Cl

O

O

NNNNEt

Et

anti cancer

NNN

MeO

MeOOMe

OMe

OMe

OMe

anti cancer OH

NP

NN

NH2

O

OR

ROO

HIV protease inhibitorR = alkyl, aryl

N

N

N NN

F

MeOOMe

OMe

anti TB

NSO

F OO

O NNN

R

R = H, F, Cl, Br, Me, Et, iPr

anti bacterial

F

F

OHN

NN

N NN R

R = H, bile acid, long alkyl chainanti fungalChem. Asian J. 2011, 6, 2696 – 2718

4. ApplicationsIAgrochemistry

N

Cl

Cl

F3CNN

R2R1

R1= H, Ph, n-Pen., n-Hex., n-Bu., t-Bu.R2= H, Ph, n-Pen., n-Hex., n-Bu., t-Bu.

Phenyl-1H-1,2,3-triazoles

insecticidal

N

NN

NHN

fungicidal

1,2,3-triazolephenylhydrazone

F

Cl

Org. Biomol. Chem., 2015, 13, 477–486

PCT Int. Appl. (2013), WO 2013037289 A1

O2N Cl

O NNN

N

N

H2Nmicrobicidal

J. Agric. Food Chem. 2006, 54, 1361-1372

4. ApplicationsFluorescent compounds

N

N NN

OEtO

NNN

NH2

N

adenine analoguesOrg. Biomol. Chem., 2014, 12, 5158

N O O

O O NN

N

O

OAc

OAc

OAc

OAc

4

BF F

Synthesis 2014, 46, 3239–3248

O

NN N

I

O

OO

12

Organogelator and fluorescentTetrahedron 71 (2015) 2124.

MeO

NNN

O ONEt

Et

N O

OO

O

fluoroionophoresChem. Commun., 2014, 50, 14167

N

O

N NN

BrH2N

NC OO

Antimicrobial and fluorescent

Eur. J. Med. Chem. 77 ,2014,145.