This document discusses regioselective approaches for alkylating 1H-1,2,4 triazole. It describes that 1H-1,2,4 triazole undergoes SN2 alkylation at the 1 position. The main challenges are obtaining single regioisomers and avoiding overalkylation. Weakly nucleophilic bases like DBU and using good leaving groups like tosylate improve regioselectivity and yield. Key methods include aminating the 4 position before alkylation or using DBU as the catalyst. Overall, DBU-catalyzed alkylation of 1H-1,2,4 triazole with tosylate as the living group provides high yields of the desired 1

1. Regioselective approaches for
1H-1,2,4 Triazole alkylation
Presented by: Parth Shah, Shalaka Nagarkar
Reg No. : PH0057
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2. Chemistry of Triazole
 Two types : 1,2,3 triazoles and 1,2,4 triazoles
4
NH
2 N
N
1
• 1 and 2 N is basic in nature and 4 N is acidic
•Lone pair of 4 N takes part in aromaticity
•Tautomerism of proton between 1 and 4 position
•Aromatic stabilization energy of 1H 1,2,4 triazole is (18.01)
4H 1,2,4 triazole (12.19) which indicates 1H is more stable
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3. Synthesis of 1,2,4 triazoles
 Two name reactions:
 Einhorn Brunner reaction: Imide with alky hydrazine to
form mixture of regioselective
1H 1,2,4 triazole
R R
R
O O O O O
O O O
AcOH +
NH NH2 + H3C NH CH3
N N N N
N N
 Pellizzari synthesis: It’s a reaction between amide and
hydrazide but the product is not regioselective
compared to Einhorn Brunner reaction
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4. Reaction mechanism
 Substitution nucleophilic reaction of SN2
type
 One transition state with pentavalent
intermediate
 Primary and secondary halides undergo
SN2
 Thermodynamically favored reaction
 Aprotic polar solvent: Inhibit tautomerism
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5. Drawback of Pellizzari reaction
 Reactants: 1: 2 : 4-Triazole (10.0 g.)
 Reagent: Sodium and methanol
 Alkylating agent: Methyl Iodide
 Reaction condition:120 o for 1 h
 Yield: 78%l-methyl-1 : 2 : 4-triazole
 Work up:precipitate unchanged 1 : 2 : 4-
triazole, m. p. 121o
 Residue distilled out
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6. 1H vs 4H alkylation on 1,2,4 triazole
 1H 1,2,4 triazole : Lower boiling
point
 Soluble in organic solvent
 Comparatively basic
 4H 1,2,4 triazole :
 Higher boiling point
 Soluble in aqueous solution
 Comparatively acidic
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7. Problems with regioselectivity
 Mixture of 1H and 4H alkylated
product
 Over alkylation leading to salt
formation
 Scale up problem for isolation
 Solutions: Amination of 4 Nitogen
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8.  2 step process:
 Alkylation of 4-aminotriazole with 4-
nitrobenzyl bromide
 sodium nitrite deamination with
evolution of nitrous oxide
 Advantage: An overall yield of >90%
from 4-aminotriazole
 Depends upon both reactants
 Replacement of 4 amino triazole by
triazole in above given reaction gives
single isomer but with poor yield of 52%
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9. DBU-weak nucleophilic base
 Alkylated 1,2,4-triazoles gives
constant 90:10 ratio either by
 changing base (NaH, K2CO3,
Cs2CO3, DBU, LiOH, NaOH,
tetramethylguanidine) or
 solvent (MeOH, THF, toluene,
CH3CN, DMF). Or
 changing electrophile (X=Cl, Br)
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10. •Regioselectivity of reaction is increased by using weak nucleophilic base
1,8 diazabicyclo[5.4.0]undec-7-ene (DBU).
•DBU (1.2 equiv.), 4-nitrobenzyl chloride (1.0 equiv.), triazole (1.1 equiv.) and
THF whereby a 93% yield of adducts in a 90:10 ratio was obtained
•successive aqueous washes increased the isomer ratio to 98:2.
•DBU is recycled and can be recovered
•DBU is water soluble
•It forms complex with HX as DBU.HX which can be seprated simply by filtration
•Purification of the isomeric mixtures of triazoles was achieved by distillation,
or silica gel chromatography or by recrystalization
•For scalling up the reaction on large scale distillation method is preferable as pure
1-alkyl-1,2,4-triazoles were obtained (>99:1) without any attempt at fractionation.
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11. 11

12.  Katritzky et al. have disclosed an improved
method for the alkylation of 1,2,4-triazole and
they give five examples of isomer ratios of 100:0
using a DMF/NaOH system
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13. Role of living group
+
 Tosylium used here in replacement of halide group is a
good living group in presence of K2CO3 as base and
Bu4N+ •Br- as catalyst using DMF as solvent with 95%
yield [6]. To further increase the yield use of DBU as
catalyst can be done
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14. Conclusion
 Regioselective alklation of 1H,1,2,4 triazole undergoes SN2
mechanism for alkylation.
 Regioselectivity for 1H position faces two main problem
isomerism and over alkylation which is affected by living
group present on alkyl substituent and catalyst used during
the process.
 Use of weakly nucleophilic base like DBU with tosylium as
living group can assure more than 95% yield of 1H product
with both tosylium and DBU both are reusable so that it can
make cost efficient process.
 DBU and tosylium salt are water soluble it can be easily
recovered by aqueous washing and filtration. Desired
compound can be seprated by distillation on scale up due to
difference in physical property of 1H and 4H triazene
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15. Refrences
 [1] POTTS . K. T.; THE CHEMISTRY OF 1,2,4-
TRIAZOLES;Tetrahedron,1960
 [2] ATKINSON. M. R.; POLYA. J. B.; J.Org.
Chem., 1952, 3418.
 [3] Katritzky et. al.; Hetrocyclic aromatic
chemistry
 [4] Balaban.A.T.; Oniciu.C.D.; Esperion
Therapeutics;2003;2777
 [5] Paul G. B., Ian F. C., Cameron J. C.;
Tetrahedron Letters 41 (2000) 1297–1301
 [6] Aouine, Younas; Faraj, Hassane;Molecules,16;
2011; 3380-3390
 [7] Chen, Wei; Chen, Chen;
Journal;33;7;2011;603-606
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16. Thank
You
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