tetrazole and triazole
TRANSCRIPT
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.