136 Combinatorial Chemistry & High Throughput Screening, 2010, Vol. 14, No. 2
Woodard and Jerome
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at reflux in 80% yield; 1H NMR (300 MHz, d-DMSO) ꢀ 2.10
in quantitative yield; H NMR (300 MHz, d-DMSO) ꢀ 2.19,
2.25 (s, 3H), 3.72, 3.84 (s, 2H), 6.67 (m, 2H), 7.05 (d, 2H,
J=8.25 Hz), 9.14, 9.25 (s, 1H). GCMS 8.85 min, m/z 189, calcd.
189.27.
(s, 3H), 3.00 (s, 2H), 4.26 (br s, 2H), 9.07 (br s, 1H).
General Procedure E. Formation of 3,5-dimethylene
1,2,4-triazoles (8) from Imidates (3) and hydrazides (6). A
solution of free imidate 3 (1.5 mmol) in 9.5 ml acetonitrile
was added to a vial containing a hydrazide 6 (1.5 mmol).
The resulting solution was stirred and heated in a sealed vial
to 50oC in a Pierce reactor overnight. The reaction was then
heated to 105oC for an additional 24 hours, except for any
reaction containing hydrazide 6l, to which 5 ml of Hunig’s
base and excess K2CO3 was added and heated for 6 hours.
The reaction was cooled and evaporated. A silica column
was done to afford pure dimethylene triazole 8. All products
were fully characterized by GCMS and 1H NMR.
Representative compounds are shown below.
8gg.
3,5-Dimethoxymethyl-1H-1,2,4-triazole.
Used
general procedure E to react imidate 3g with hydrazide 6g in
66% yield; 1H NMR (300 MHz, CDCl3) ꢀ 3.52 (s, 6H), 4.65 (s,
4H). GCMS 4.94 min, m/z 156, calcd. 157.18.
8hs.
3-Carbomethoxymethyl-5-(1-(N-benzylcarboxyl-
Used
amino)-3-carboxamide-propyl)-1H-1,2,4-triazole.
general procedure E to react imidate 3h with hydrazide 6s in
95% yield; 1H NMR (300 MHz, CDCl3) ꢀ 2.30 (m, 2H), 3.79 (s,
3H), 3.89 (m, 2H), 3.91 (m, 2H), 5.02 (m, 1H), 5.09 (s, 2H),
5.51 (m, 2H), 6.05 (m, 1H), 7.35 (m, 5H).
8iu. Bis(3-acetamide-5-thiomethyl-1H-1,2,4-triazole).
Used general procedure E to react imidate 3i with hydrazide
6u in 38% yield; H NMR (300 MHz, d-DMSO) ꢀ 3.38 (s,
4H), 3.92 (s, 4H), 7.15, 7.56 (br s, 4H).
8ab. 3-Methyl-5-ethyl-1H-1,2,4-triazole. Used general
procedure E to react imidate 3a with hydrazide 6b in 71% yield;
1H NMR (300 MHz, CDCl3) ꢀ 1.38 (t, 3H, J=7.55 Hz), 2.48 (s,
3H), 2.81 (q, 2H, J=7.65 Hz), 6.83 (br s, 1H). GCMS 3.14 min,
m/z 111, calcd. 111.17.
1
REFERENCES
8ah. 3-Methyl-5-carbomethoxymethyl-1H-1,2,4-triazole.
[1]
Review with 181 refs: Al-Masoudi, A.; Al-Soud, Y.A.; Al-Salihi,
N.J.; Al-Masoudi, N.A. 1,2,4-Triazoles: Synthetic Approaches.
Chem. Het. Cmpds., 2006, 42 (11), 1377-1403.
Bayrak, H.; Demirbas, A.; Karaoglu, S.A.; Demirbas, N. Synthesis
of some new 1,2,4-triazoles, their Mannich and Schiff bases and
evaluation of their antimicrobial activities. Eur J. Med. Chem.,
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Sharma, S.; Gangal, S.; Rauf, A.; Zahin, M. Synthesis, antibacterial
and antifungal activity of some novel 3,5-disubstituted-1H-1,2,4-
triazoles. Arch. Pharm. Chem. Life Sci., 2008, 341, 714-720.
Chen, C.; Dagnino, R.; Huang, C.Q.; McCarthy, J.R.; Grigoriadis,
D.E. 1-Alkyl-3-amino-5-aryl-1H-[1,2,4]triazoles: novel synthesis
Used general procedure E to react imidate 3a with hydrazide 6h
84% yield; 1H NMR (300 MHz, CDCl3) ꢀ 2.54 (s, 3H), 3.80 (s,
3H), 3.94 (s, 2H), 4.31 (br s, 1H). GCMS 4.76 min, m/z 155,
[2]
calcd. 155.16.
8bj. 3-Ethyl-5-hydroxymethyl-1H-1,2,4-triazole. Used
general procedure E to react imidate 3b with hydrazide 6j in
82% yield; 1H NMR (300 MHz, d-DMSO) ꢀ 1.37 (t, 3H, J=7.55
Hz), 2.83 (q, 2H, J=7.65 Hz), 4.81 (s, 2H). GCMS 5.59 min, m/z
127, calcd. 127.15.
[3]
[4]
via
cyclization
of
N-Acyl-S-methylisothioureas
with
8bm*. 3-Ethyl-5-aminomethyl-1H-1,2,4-triazole. Used
general procedure E to react imidate 3b with hydrazide 6m,
followed by deprotection of the BOC with TFA in 75% overall
yield; 1H NMR (300 MHz, d-DMSO) ꢀ 1.24 (t, 3H, J=7.55 Hz),
2.74 (q, 2H, J=7.65 Hz), 4.04 (m, 2H), 8.38 (br s, 2H).
alkylhydrazines and their potent corticotropin-Releasing factor-1
(CRF1) receptor antagonist activities. Bioorg. Med. Chem. Lett.,
2001, 11, 3165-3168.
Jenkins, S.M.; Wadsworth, H.J.; Bromidge, S.; Orlek, B.S.;
Wyman, P.A.; Riley, G.J.; Hawkins, J. Substituent variation in
azabicyclic triazole-and tetrazole-based muscarinic receptor
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Thompson, S.K.; Eppley, A.M.; Frazee, J.S.; Darcy, M.G.; Lum,
R.T.; Tomaszeck, T.A.; Ivanoff, L.A.; Morris, J.F.; Sternberg, E.J.;
Lambert, D.M.; Fernandez, A.V.; Petteway, S.R.; Meek, T.D.;
Metcalf, B.W.; Gleason, J.G. Synthesis and antiviral actvity of a
novel class of HIV-1 protease inhibitors containing a heterocyclic
P1’-P2’ amide bond isostere. Bioorg. Med Chem. Lett., 1994, 4,
2441-2446.
[5]
[6]
8ci. 3-Isovaleryl-5-cyanomethyl-1H-1,2,4-triazole. Used
general procedure E to react imidate 3c with hydrazide 6i in
80% yield; 1H NMR (300 MHz, CDCl3) ꢀ 1.01 (d, 6H, J=6.65
Hz), 2.16 (m, 1H), 2.72 (d, 2H, J=7.25 Hz), 3.92 (s, 2H). GCMS
6.26 min, m/z 164, calcd. 164.20.
8ct. 3-Isovaleryl-5-(N-methylene-1,2,4-triazole)-1H-1,2,4-
[7]
[8]
[9]
Burrell, G.; Evans, J.M.; Hadley, M.S.; Hicks, F; Stemp, G.
Benzopyran potassium channel activators related to cromakalim-
heterocyclic amide replacements at position 4. Bioorg. Med. Chem.
Lett., 1994, 4, 1285-1290.
Tully, W.R.; Gardner, C.R.; Gillespie, R.J.; Westwood, R. 2-
(Oxadiazolyl)- and 2-(thiazolyl)imidazo[1,2-a]pyrimidines as
agonists and inverse agonists at benzodiazepine receptors. J. Med.
Chem., 1991, 34, 2060-2067.
Duncia, J.V.; Santela, J.B. III; Higley, A.; VanAtten, M.K.; Weber,
P.C.; Alexander, R.S.; Kettner, C.A.; Pruitt, J.R.; Liauw, A.Y.;
Quan, M.L.; Knabb, R.M.; Wexler, R.R. Pyrazoles, 1,2,4-triazoles,
and tetrazoles as surrogates for cis-amide bonds in boronate ester
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Wang, X.C.; Wang, J.K.; Da, Y.X.; Quan, Z.J.; Zong, Y.X. A novel
traceless route to synthesize 3,5-disubstituted-1,2,4-triazoles on
PEG6000. Tet. Lett., 2005, 46, 8479-8481.
triazole. Used general procedure E to react imidate 3c with
1
hydrazide 6t in 81% yield; H NMR (300 MHz, d-DMSO) ꢀ
0.87 (d, 6H, J=6.65 Hz), 1.95 (m, 1H), 2.51 (d, 2H, J=7.25 Hz),
5.40 (s, 2H), 7.95 (s, 1H), 8.58 (s, 1H). GCMS 7.78 min, m/z
206, calcd. 206.25.
8de.
3-(Methylthio)methyl-5-benzyl-1H-1,2,4-triazole.
Used general procedure E to react imidate 3d with hydrazide 6e
in 69% yield; 1H NMR (300 MHz, CDCl3) ꢀ 2.16 (s, 3H), 3.78
(s, 2H), 4.15 (s, 2H), 7.32 (m, 5H). GCMS 8.46 min, m/z 219,
calcd. 219.30.
[10]
[11]
[12]
8el. 3-Benzyl-5-(di-t-butyl phosphonomethyl)-1H-1,2,4-
triazole. Used general procedure E to react imidate 3e with
hydrazide 6l in 51% yield; 1H NMR (300 MHz, CDCl3) ꢀ 1.46
(s, 18H), 3.28 (d, 2H, J=20.75 Hz), 4.09 (s, 2H), 7.31 (m, 5H).
19F NMR (d-DMSO) ꢀ14.55 (s).
Wang, X.C.; Wang, J.K.; Dong, Q.W.; Zong, Y.X. Liquid-phase
traceless synthesis of 3,5-disubstituted 1,2,4-triazoles. Synlett.,
2005, 2595-2598.
Samanta, S.K.; Yli-Kauhaluoma, J. Polymer-supported 1,3-
oxazolium-5-olates: synthesis of 1,2,4-triazoles. J. Comb. Chem.,
2005, 7, 142-146.
8fa.
3-(4-Hydroxybenzyl)-5-methyl-1H-1,2,4-triazole.
Used general procedure E to react imidate 3f with hydrazide 6a