tetrazole and triazole

43
Shrikant G. Pharande Tetrazoles and Triazoles Synthesis and applications

Upload: shrikant-pharande

Post on 09-Apr-2017

117 views

Category:

Science


2 download

TRANSCRIPT

Page 1: Tetrazole and triazole

Shrikant G. Pharande

Tetrazoles and TriazolesSynthesis and applications

Page 2: Tetrazole and triazole

NN N

N

R

R11

23

45

NN N

NH

R

1

2

3

45

1, 5 di-substituted tetrazole

5 -substituted tetrazole

Tetrazoles

Page 3: Tetrazole and triazole

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

NN

NH

N

Page 4: Tetrazole and triazole

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

- they are unknown to nature

Page 5: Tetrazole and triazole

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

Page 6: Tetrazole and triazole

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

Page 7: Tetrazole and triazole

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

Page 8: Tetrazole and triazole

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

- thermal stability is high

Page 9: Tetrazole and triazole

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

Page 10: Tetrazole and triazole

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

Page 11: Tetrazole and triazole

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%

Page 12: Tetrazole and triazole

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

Page 13: Tetrazole and triazole

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

Page 14: Tetrazole and triazole

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)

Page 15: Tetrazole and triazole

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)

Page 16: Tetrazole and triazole

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)

Page 17: Tetrazole and triazole

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.

Page 18: Tetrazole and triazole

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

Page 19: Tetrazole and triazole

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

Page 20: Tetrazole and triazole

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

Page 21: Tetrazole and triazole

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.

Page 22: Tetrazole and triazole

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.

Page 23: Tetrazole and triazole

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

Page 24: Tetrazole and triazole

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

Page 25: Tetrazole and triazole

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

Page 26: Tetrazole and triazole

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

Page 27: Tetrazole and triazole

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

Page 28: Tetrazole and triazole

1,2,3 triazoles

NH

NN

1

2

34

5

Page 29: Tetrazole and triazole

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

Page 30: Tetrazole and triazole

1.Introduction

NN

N

R1

RMedicinal chemistry

Agrochemicals

Fluorescent materials

dyes

Polymer chemistry

Chem. Rev. 2008, 108, 2952–3015

Page 31: Tetrazole and triazole

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

Page 32: Tetrazole and triazole

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

Page 33: Tetrazole and triazole

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

Page 34: Tetrazole and triazole

2. SynthesisUgi- triazoles – 6 component ugi

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

81-92%

Page 35: Tetrazole and triazole

2. SynthesisUgi- triazoles – peptoid mimics

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

Page 36: Tetrazole and triazole

2. SynthesisUgi- triazoles – fused triazole

Tetrahedron Lett. 2004, 45, 8439

86-98%7 examples

Page 37: Tetrazole and triazole

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

Page 38: Tetrazole and triazole

2. SynthesisUgi- triazoles – macrocycles in pot

Oxazole intermediate

Org. Lett., 2006, 8, 4145

Page 39: Tetrazole and triazole

2. SynthesisUgi- triazoles – click and post condensation

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

Page 40: Tetrazole and triazole

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

Page 41: Tetrazole and triazole

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

Page 42: Tetrazole and triazole

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

Page 43: Tetrazole and triazole

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.