Synthesis of 3-aryl-5-methyl 4-substituted [1,2,4]triazoles

Article abstract of DOI:10.1080/00397910600638994

Treatment of N -substituted acetamides with oxalyl chloride generates imidoyl chlorides, which react readily with aryl hydrazides. Following cyclization, triazoles can easily be obtained in moderate to good yields. 5-Methyl triazoles can be further functionalized through α-lithiation and subsequent reaction with an electrophile. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600638994

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Synthesis of 3‐Aryl‐5‐methyl 4‐Substituted
[1,2,4]Triazoles
Johan Lindström a & Martin H. Johansson a
a Medicinal Chemistry, Local Discovery CNS and Pain Control , Astra Zeneca
Research and Development Södertälje , Södertälje, Sweden
Published online: 16 Feb 2007.
To cite this article: Johan Lindström & Martin H. Johansson (2006) Synthesis of 3‐Aryl‐5‐methyl 4‐Substituted
[1,2,4]Triazoles, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:15, 2217-2229, DOI: 10.1080/00397910600638994
To link to this article: http://dx.doi.org/10.1080/00397910600638994
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Synthetic Communicationsw, 36: 2217–2229, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600638994
Synthesis of 3-Aryl-5-methyl 4-Substituted
[1,2,4]Triazoles
¨
Johan Lindstrom and Martin H. Johansson
Medicinal Chemistry, Local Discovery CNS and Pain Control,
¨ ¨ ¨ ¨
Astra Zeneca Research and Development Sodertalje, Sodertalje, Sweden
Abstract: Treatment of N-substituted acetamides with oxalyl chloride generates
imidoyl chlorides, which react readily with aryl hydrazides. Following cyclization,
triazoles can easily be obtained in moderate to good yields. 5-Methyl triazoles can
be further functionalized through a-lithiation and subsequent reaction with an
electrophile.
Keywords: Imidoyl chloride, a-lithiation, triazole
Triazoles are important five-membered heterocyclic structures. They have
found wide use in medicinal chemistry as common structural motifs acting
as peptidomimetic moieties and as hydrogen bond acceptors.[1] During a
drug-optimization program, we needed to find a simple and mild method for
preparing 5-methyl [1,2,4]triazoles. A recently described method involves
the use of N,N dimethyl formamide dimethyl acetals, yielding triazoles in a
one-pot reaction with good yields.[2] However, we required a method where
the substituents of the 3- and 5-positions could easily be varied using commer-
cially available starting materials. A more common approach is the use of
secondary amides as starting materials and the subsequent conversion of the
amide to an activated electrophile. Conversion of amides to electrophilic
species usually requires the use of dehydrating agents (e.g., SOCl2,[3]
PCl5 or POCl3,[5] the use of O-alkylating reagents such as Me3OBF4;[6] or
[4]
Received in the UK 7, October 2005
Address correspondence to Martin H. Johansson, Medicinal Chemistry, Local
¨ ¨
Discovery CNS and Pain Control, Astra Zeneca Research and Development Sodertalje,
¨
¨
SE-151 85 Sodertalje, Sweden. Fax: þ46 8 553 28877; E-mail: martin.h.johansson@
astrazeneca.com
2217

¨
J. Lindstrom and M. H. Johansson
2218
Scheme 1. Synthesis of 3-aryl-5-methyl 4-substituted [1,2,4]triazoles.
conversion over several steps to thioimidates.[7] Usually excess reagent must
be removed before continuation of the synthesis. We desired a mild method
where the reagents could be used in stoichiometric amounts or could easily
be removed. Inspired by a report where imidoyl chlorides were prepared in
situ from secondary amides through treatment with oxalyl chloride,[8] we
envisioned that these reactive intermediates could be treated with hydrazides
and cyclized, thus allowing for a possible one-pot preparation of the desired
triazoles.
Lateral or a-lithiation of methyl or alkyl substituted heteroaromatic ring
sytems is an efficient and common way of functionalizing these structures.
There are countless examples of this methodology in the literature; however,
there is only one previous example of these type of reactions with triazoles.[9]
This is somewhat surprising when considering the amount of work done on
other 5-ring heteroaromatic systems (e.g., thiadiazoles[10] and imidazoles[11]).
Here we report the mild and facile synthesis of 5-methyl [1,2,4]triazoles
(Scheme 1) and the following lithiation and subsequent reaction with
electrophiles (Schemes 2 and 3).
RESULTS
N-alkyl substituted acetamides, after treatment with oxalyl chloride, generally
gave good yields of the corresponding [1,2,4]triazoles using both electron-rich
and electron-poor (het)aryl hydrazides (Table 1). An exception was with
N-tert-butyl acetamide, which did not give any product. Gas evolution was
observed when N-tert butyl acetamide was treated with oxalyl chloride,
which indicated that the imidoyl chloride was formed, suggesting it was too
sterically hindered to further react with the hydrazide. The reaction with
Scheme 2. Lithiation and alkylation of 3-phenyl-4,5-dimethyl[1,2,4]triazole.

3-Aryl-5-methyl 4-Substituted [1,2,4]Triazoles
2219
Scheme 3. Alkylation of 3-phenyl-4,5-dimethyl[1,2,4]triazole.
N-aryl acetamides was limited in scope; the electronic nature of the aryl
substituent greatly influenced the outcome of the reaction. An activating
electron-donating group on the aryl ring is necessary for the reaction with
oxalyl chloride. N-phenyl acetamide and N-4-nitrophenyl acetamide failed
to react with oxalyl chloride at 08C and 208C as witnessed by the lack of
gas evolution. When benzhydrazide was added to this mixture, 1,2-dibenzoyl-
hydrazine was isolated as the major product, which was identical to the
material obtained when benzhydrazide alone is treated with oxalyl chloride.[12]
In most cases, the triazoles could be isolated without chromatographic
purification through recrystallization. No isolation was necessary for any inter-
mediate, and the reaction could be conducted in one flask with only a change of
reaction solvent required before the cyclization step. The method reported here
allows easy access to 4- and 5-alky substituted [1,2,4]triazoles. As a represen-
tative triazole, 4,5-dimethyl-3-phenyl [1,2,4]triazole was used when screening
different bases for the metalation. To determine the efficiency of the metala-
tion, benzyl bromide was used as the electrophile. LDA and n-Buli were
equally efficient as bases but sec-Buli in the presence of TMEDA
(N,N,N0,N0-tetramethylethylenediamine)[13] proved to be the most efficient
Table 1.
Entry
R1
R2
Yielda (%)
1
2
methyl
methyl
methyl
n-butyl
benzyl
phenyl
64
54
56
59
87
65
32
49
0
4-nitrophenyl
4-dimethylaminophenyl
phenyl
3
4
5
phenyl
phenyl
6
cyclohexyl
4-methoxyphenyl
4-methoxyphenyl
phenyl
7
4-nitrophenyl
4-dimethylaminophenyl
phenyl
8
9
10
11
12
13
14
tert-butyl
phenyl
phenyl
0
4-nitrophenyl
4-nitrophenyl
4-pyridyl
0
4-nitrophenyl
methyl
methyl
0
50
27
3-pyridyl
aIsolated yield.

¨
J. Lindstrom and M. H. Johansson
2220
Table 2.
Entry
Base
Temperature (8C)
Yielda (%)
1
2
3
4
5
6
7
8
sec-BuLi þ TMEDA
LDA
n-BuLi
278
278
278
278
278
278
278
0
79
49
49
8
KtBuO þ n-BuLi
KHMDS þ 18-crown-6
KtBuO þ DMSO
KtBuO þ 18-crown-6
n-BuLi
7
0
0
0
aIsolated yield.
metalating reagent (Table 2). The reactions were conducted in THF at –788C.
The reaction was equally efficient in diethyl ether but the triazoles had lower
solubility in that solvent as compared to THF.
Having found a suitable base, a range of electrophiles were used in the
functionalization of 4,5-dimethyl-3-phenyl 1,2,4-triazole (Table 3). Reactive
halides gave products in good yields. Probably due to competing deprotona-
tion, cyclohexanone (entry 3, Table 3) and diethyl chlorophosphate (entry 5,
Table 3) gave lower yields, whereas diphenyldisulphide (entry 4, Table 3)
gave a mixture of mono- and disulphenylated products (23 and 24). When
the 3-position of the triazole had an electron-rich substituent, an improved
reactivity was observed (cf. entries 1 and 7) (Figure 1).
In conclusion, we have developed a method where triazoles can easily be
prepared from a range of N-substituted acetamides and hydrazides through the
reaction with oxalylchloride. In addition, we have shown that methyl triazoles
can readily be lithiated with sec-BuLi together with TMEDA and that these
reactive species can be reacted with a range of electrophiles, thus allowing
further functionalizing of the triazoles.
Table 3.
Entry
Electrophile
R
Yielda (%) Product
61
1
2
3
4
5
6
7
8
9
Benzylbromide
Methyl benzoate
Cyclohexanone
Diphenyldisulphide
Phenyl
Phenyl
Phenyl
Phenyl
63
20
1
2
3 1 4
5
6
25 þ 11
20
79
Diethyl chlorophosphate Phenyl
Allylbromide
Phenyl
Benzylbromide
Benzylbromide
Benzylbromide
p-(dimethylamino)phenyl 75
p-nitrophenyl
4-pyridyl
0
12
aIsolated yield.

3-Aryl-5-methyl 4-Substituted [1,2,4]Triazoles
2221
Figure 1.
EXPERIMENTAL
Melting points were measured on a Bu¨chi melting-point B-545 apparatus and
are uncorrected. NMR spectra were recorded either on a Bruker DPX400
operating at 400 MHz and 268C, equipped with a 5-mm QNP probe with
z-gradients, or a Bruker Avance 600 operating at 600 MHz and 300 K,
equipped with a 5-mm BBI probe with z-gradients. The residual solvent
signal or TMS was used as reference. All chemical shifts are in parts per
million (ppm) on the delta scale, and the fine splitting of the signals
appeared in the recordings (s: singlet, d: doublet, t: triplet, m: multiplet).
LC-MS was performed on a Waters Alliance 2795 system including
degasser, autosampler, quaternary pump, 6-position column switch, and a
column oven. In addition, UV (PDA2996, Waters) and evaporative light-
scattering detectors (ELSD, Sedex75, Sedere, France) were connected to the
system. A linear binary gradient was used starting at 100% A: 10 mM of
NH4OAc in 5% MeCN, and ending at 100% B: MeCN, after 4.5 min. The
column used was a Waters XTerra MS C8, 3.0 ꢀ 50 mm, 3 mm, which was
run at a flow rate of 1 ml/min. The MS system was a Waters ZQ with an elec-
trospray ion source. The capillary voltage and the sample cone voltage were
set to 3.2 kV and 30 V, respectively. The MS was scanned at 120–700 m/z
in both positive and negative mode. HRMS was recorded on a Waters
Q-TOF Micro system with leucine-enkephalin as lock mass (556.2771).
Purity analyses were run on an Agilent HP1100 system with an XTerra
MS C8, 3.0 ꢀ 100, 3-mm column, which was run at a flow rate of 1 ml/
min. A linear gradient was used starting at 100% A: 10 mM of NH4OAc in
5% MeCN, and ending at 100% B: MeCN, after 7.0 min. Flash-column chrom-
atography was performed on an ISCO Flash Companion with RediSep normal
phase disposable flash columns of various sizes (4 g, 12 g, 40 g, 80 g, or 120 g).
Preparative chromatography was performed on a Waters Autopurification
UV system with PDA detector, equipped with a Waters XTerra Prep MS C8,

¨
J. Lindstrom and M. H. Johansson
2222
10 mm, 19 ꢀ 300 mm column. An adjusted gradient (depending on retention
time) was used, running 0–13 min with eluents A: 0.1M of NH4OAc in
H2O with 5% MeCN and B: MeCN. Products were freeze-dried on a Christ
Alpha 2-4 LD-2 freeze-drier.
General Method for the Formation of Substituted
4H-[1,2,4]Triazoles
Oxalylchloride (1 eq) was added dropwise to a solution of amide (1 eq, 0.14–
0.2 M in CH2Cl2) and 2,6-lutidine (2 eq) at 08C under a nitrogen atmosphere.
After stirring for about 40 min, hydrazide was added, and the solution was
allowed to reach rt and was stirred for a couple of hours, still under
nitrogen. When the reaction was finished, the volatiles were removed in
vacuo, and the residue was dissolved in a saturated aqueous solution of
NaHCO3 and refluxed. The water phase was then extracted, and the organic
phase was dried or acidified with 1 M HCl and extracted prior to drying.
The crude product was concentrated in vacuo and purified by recrystallization
or flash-column chromatography.
3,4-Dimethyl-5-phenyl-4H-[1,2,4]triazole
Oxalylchloride (1.72 ml, 20 mmol) was added to a solution of N-methyl-
acetamide (1.46 g, 20 mmol) and 2,6-lutidine (4.66 ml, 40 mmol) in CH2Cl2
(100 ml) at 08C under heavy gas evolution. The mixture was stirred for
30 min, and benzoic acid hydrazide (2.72 g, 20 mmol) was added. The
reaction mixture was stirred for 3.5 h at rt, and then the volatiles were
removed under reduced pressure. The residue was dissolved in NaHCO3(sat)
(100 ml) and refluxed for 45 min at 1008C. After cooling to rt, the water
phase was extracted three times with CHCl3. The organic phase was dried
over MgSO4, and concentrated. Recrystallization from EtOAc gave the title
compound as light pink crystals, 2.21 g (64%). dH (400 MHz, CDCl3): 2.53
(3, s, C-CH3), 3.60 (3, s, N-CH3), 7.50–7.52 (3, m, Ar-H), 7.62–7.64 (2, m,
Ar-H); 13C (100 MHz, CDCl3) d 11.0, 31.1, 127.4, 128.6, 128.8, 129.8,
152.3, 154.7; LCMS (EI) m/z 174.1 (MHþ). Mp 138–1398C. HRMS (ES)
calcd. for C10H11N3 (M þ H) 174.1029, found 174.1031.
3,4-Dimethyl-5-(4-nitrophenyl)-4H-[1,2,4]triazole
Oxalylchloride (1.72 ml, 20 mmol) was added to a solution of N-methyl-
acetamide (1.46 g, 20 mmol) and 2,6-lutidine (4.66 ml, 40 mmol) in CH2Cl2
(100 ml) at 08C under heavy gas evolution. The mixture was stirred for
40 min, and 4-nitrobenzoic acid hydrazide (3.62 g, 20 mmol) was added.

3-Aryl-5-methyl 4-Substituted [1,2,4]Triazoles
2223
The reaction mixture was stirred for 2 h at rt, and then the volatiles were
removed under reduced pressure. The residue was dissolved in NaHCO3(sat)
(100 ml) and refluxed for 1 h at 1008C. After cooling to rt, the water phase
was extracted three times with CHCl3. Then the waterphase was saturated
with NaCl and extracted another three times with CHCl3. The combined
organic phases were then washed once with 1 M HCl (100 ml), dried over
MgSO4, and concentrated. Recrystallization from EtOAc gave the title
compound as brown crystals, 2.37 g (54%). dH (400 MHz, CDCl3): 2.57
(3, s, N-CH3), 3.68 (3, s, CCH3), 7.88 (2, d, J ¼ 8.5 Hz, Ar-H), 8.38 (2, d,
J ¼ 8.5 Hz, Ar-H). Mp 231–2328C. HRMS (ES) calcd. for C10H10N4O2
(M þ H) 219.0880, found 219.0882.
[4-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-dimethyl-amine
Oxalylchloride (1.72 ml, 20 mmol) was added to a solution of N-methyl-
acetamide (1.46 g, 20 mmol) and 2,6-lutidine (4.66 ml, 40 mmol) in CH2Cl2
(100 ml) at 08C under heavy gas evolution. The mixture was stirred for
40 min, and 4-dimethylamino benzoic acid hydrazide (3.58 g, 20 mmol) was
added. The reaction mixture was stirred for 4.5 h at rt, and then the volatiles
were removed under reduced pressure. The residue was dissolved in
NaHCO3(sat) (100 ml) and refluxed for 1 h at 1008C. After cooling to rt, the
water phase was extracted three times with CHCl3. The combined organic
phases were then washed once with 1 M HCl (100 ml), dried over MgSO4,
and concentrated. Recrystallization from EtOAc gave the title compound as
pink crystals, 2.42 g (56%). dH (400 MHz, CDCl3): 2.49 (3, s, N-CH3), 3.03
[6, s, N-(CH3)2], 3.58 (3, s, CCH3), 6.78 (2, d, J ¼ 8.9 Hz, Ar-H), 7.50
(2, d, J ¼ 8.9 Hz, Ar-H). Mp 173–1748C. HRMS (ES) calcd. for C12H16N4
(M þ H) 217.1448, found 217.1453.
4-(n-Butyl)-3-methyl-5-phenyl-4H-[1,2,4]triazole
Oxalylchloride (1.72 ml, 20 mmol) was added to a solution of N-butyl-
acetamide (2.56 g, 20 mmol) and 2,6-lutidine (4.66 ml, 40 mmol) in CH2Cl2
(100 ml) at 0 8C under heavy gas evolution. The mixture was stirred for
40 min, and benzoic acid hydrazide (2.72 g, 20 mmol) was added. The
reaction mixture was stirred for 3 h at rt, and then the volatiles were
removed under reduced pressure. The residue was dissolved in NaHCO3(sat)
(100 ml) and refluxed for 1 h at 1008C. After cooling to rt, the water phase
was extracted three times with CHCl3. The combined organic phases were
then washed once with 1 M HCl (100 ml), dried over MgSO4, and concen-
trated. Flash-column chromatography on silica gel, with CH2Cl2/
MeOH þ 1% TEA as eluents, gave the title compound as an orange oil,
2.54 g (59%). dH (400 MHz, CDCl3): 0.82–0.86 (3, t, J ¼ 7.6 Hz,

¨
J. Lindstrom and M. H. Johansson
2224
-CH2CH3), 1.21–1.26 (2, m, J ¼ 7.6 Hz, -CH2-), 1.56–1.62 (2, m, J ¼ 7.3 Hz,
-CH2-), 2.52 (3, s, CH3), 3.89–3.93 (2, t, J ¼ 7.8 Hz, -CH2-), 7.47–7.50 (3, m,
Ar-H), 7.56–7.58 (2, m, Ar-H). HRMS (ES) calcd. for C13H17N3 (M þ H)
216.1500, found 216.1499.
Benzyl-3-methyl-5-phenyl-4H-[1,2,4]triazole
Oxalylchloride (1.72 ml, 20 mmol) was added to a solution of N-benzyl-
acetamide (2.98 g, 20 mmol) and 2,6-lutidine (4.66 ml, 40 mmol) in CH2Cl2
(100 ml) at 08C under heavy gas evolution. The mixture was stirred for
40 min, and benzoic acid hydrazide (2.72 g, 20 mmol) was added. The
reaction mixture was stirred for 3 h at rt, and then the volatiles were removed
under reduced pressure. The residue was dissolved in NaHCO3(sat) (100 ml)
and refluxed for 2 h at 100 8C. After cooling to rt, the water phase was
extracted three times with CHCl3. The water phase was saturated with NaCl
and extracted another three times with CHCl3. The combined organic phases
were then washed once with 1 M HCl (100 ml), dried over MgSO4, and concen-
trated. Recrystallization from EtOAc gave the title compound as orange
crystals, 4.35 g (87%). dH (400 MHz, CDCl3): 2.38 (3, s, CH3), 6.99 (2, d,
J ¼ 6.6 Hz, CH2), 7.29–7.48 (7, m, Ar-H), 7.52–7.55 (3, m, Ar-H). Mp 74–
758C. HRMS (ES) calcd. for C16H15N3 (M þ H) 250.1344, found 250.1336.
4-Cyclohexyl-3-methyl-5-phenyl-4H-[1,2,4]triazole
Oxalylchloride (0.43 ml, 5 mmol) was added to a solution of N-cyclohexylacet-
amide (0.71 g, 5 mmol) and 2,6-lutidine (1.16 ml, 10 mmol) in CH2Cl2 (25 ml)
at 08C under heavy gas evolution. The mixture was stirred for 40 min, and then
benzoic acid hydrazide (0.68 g, 5 mmol) was added. The reaction mixture was
stirred for 1.5 h at rt, and then the volatiles were removed under reduced
pressure. The residue was dissolved in NaHCO3(sat) (25 ml) and refluxed for
2 h at 1008C. After cooling to rt, the water phase was extracted three times
with CHCl3. The organic phase was dried over MgSO4 and concentrated,
which gave a light brown oil. Flash-column chromatography on silica gel,
with CH2Cl2/MeOH þ 1% TEA as eluents, gave the title compound as green
crystals, 0.79 g (65%). dH (400 MHz, CDCl3): 1.13–1.28 (3, m, cyclohexyl-
H), 1.65–1.75 (2, m, cyclohexyl-H), 1.83–1.90 (5, m, cyclohexyl-H), 2.65
(3, s, C-CH3), 3.99–4.07 (1, m, N-CH), 7.49–7.53 (5, m, Ph). Mp 124–
1258C. HRMS (ES) calcd. for C15H19N3 (M þ H) 242.1653, found 242.1657.
4-(4-Methoxyphenyl)-3-methyl-5-(4-nitrophenyl)-4H-[1,2,4]triazole
Oxalylchloride (1.72 ml, 20 mmol) was added to a solution of N-(4-methoxy-
phenyl)-acetamide (3.30 g, 20 mmol) and 2,6-lutidine (4.66 ml, 40 mmol) in

3-Aryl-5-methyl 4-Substituted [1,2,4]Triazoles
2225
CH2Cl2 (140 ml) at 08C under heavy gas evolution. The mixture was stirred
for 40 min, and 4-nitrobenzoic acid hydrazide (3.62 g, 20 mmol) was added.
The reaction mixture was stirred for 3.5 h at rt, and then the volatiles were
removed under reduced pressure. The residue was dissolved in NaHCO3(sat)
(140 ml) and refluxed for 1 h at 1008C. After cooling to rt, the water phase
was extracted three times with CHCl3. The organic phase was dried over
MgSO4 and concentrated. Recrystallization from EtOAc gave the title
compound as light brown crystals, 2.01 g (32%). dH (600 MHz, CDCl3):
2.37 (3, s, C-CH3), 3.90 (3, s, PhOCH3), 7.03–7.04 (2, d, J ¼ 9.0 Hz,
Ar-H), 7.12–7.14 (2, d, J ¼ 9.0 Hz, Ar-H), 7.64 (2, d, J ¼ 9.1 Hz, Ar-H),
8.14 (2, d, J ¼ 9.1 Hz, Ar-H). Mp 186–1878C. HRMS (ES) calcd. for
C16H14N4O3 (M þ H) 311.1141, found 311.1144.
f4-[4-(4-Methoxyphenyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-phenylg-
dimethyl-amine
Oxalylchloride (1.72 ml, 20 mmol) was added to a solution of N-(4-methoxy-
phenyl)-acetamide (1.46 g, 20 mmol) and 2,6-lutidine (4.66 ml, 40 mmol) in
CH2Cl2 (100 ml) at 08C under heavy gas evolution. The mixture was stirred
for 40 min, and 4-dimethylamino-benzoic acid hydrazide (3.58 g, 20 mmol)
was added. The reaction mixture was stirred for 4 h at rt. Then the volatiles
were removed under reduced pressure. The residue was dissolved in
NaHCO3(sat) (100 ml) and refluxed for 1.5 h at 1008C. After cooling to rt,
the water phase was extracted three times with CHCl3. The combined
organic phases were then washed once with 1 M HCl (100 ml), dried over
MgSO4, and concentrated. Flash column chromatography on silica gel, with
CH2Cl2/MeOH þ 1% TEA as eluent, gave the title compound as yellow
crystals, 3.01 g (49%). dH (400 MHz, CDCl3): 2.31 (3, s, C-CH3), 2.95 [6, s,
N-(CH3)2], 3.88 (3, s, O-CH3), 6.57 (2, d, J ¼ 8.8 Hz, Ar-H), 6.99 (2, d,
J ¼ 8.8 Hz, Ar-H), 7.13 (2, d, J ¼ 8.8 Hz, Ar-H), 7.30 (2, d, J ¼ 9.1 Hz, Ar-H).
Mp 172–1738C. HRMS (ES) calcd. for C18H20N4O (M þ H) 309.1710,
found 309.1715.
General Procedure: Alkylation of 3,4-Dimethyl-5-aryl-4H-
[1,2,4]triazoles
sec-Butyllithium (solution in cyclohexane) was added to a solution of
[1,2,4]triazole and dry THF/TMEDA (30 : 1 v/v; 50 mM [1,2,4]triazole) at
2788C and stirred under a nitrogen atmosphere. The mixture was stirred
for 30 min, and the electrophile was then injected to the reaction at 2788C
under nitrogen. The reaction mixture was allowed to warm to rt and stirred
overnight under nitrogen. The reaction was quenched with NH4Cl(sat)
(10 ml), and the aqueous phase was extracted with EtOAc (20 ml each time)

¨
J. Lindstrom and M. H. Johansson
2226
until TLC showed no UV absorbing substance left in the aqueous phase. The
combined extracts were concentrated under reduced pressure in vacuo, and the
crude product was purified by flash column chromatography on silica gel
(CH2Cl2:MeOH þ 1% TEA, gradient elution) to give the alkylated 3,4-
dimethyl-5-aryl-4H-[1,2,4]triazoles.
4-Methyl-3-phenethyl-5-phenyl-4H-[1,2,4]triazole
This was prepared by the general method, using sec-BuLi (0.85 ml, 1.1 mmol,
1.3 M in cyclohexane), 3,4-dimethyl-5-phenyl-4H-[1,2,4]triazole (0.173 g,
1 mmol), TMEDA (0.66 ml, 4.4 mmol), benzylbromid (0.14 ml, 1.2 mmol),
and dry THF (20 ml). The title compound was obtained as white crystals,
0.16 g (61%). dH (400 MHz, CDCl3): 3.10–3.13 (2, t, J ¼ 7.5 Hz, CH2),
3.20–3.23 (2, t, J ¼ 7.8 Hz, CH2), 3.29 (3, s, CH3), 7.21–7.23 (3, m, Ar-
H), 7.30–7.33 (2, m, Ar-H), 7.49–7.51 (3, m, Ar-H), 7.57–7.59 (2, m, Ar-
H); 13C (100 MHz, CDCl3) d 27.5, 30.8, 34.0, 126.6, 127.3, 128.6, 128.8,
129.9, 140.4, 154.7, 155.0; LCMS (EI) m/z 264.1 (MHþ). Mp 145–1468C.
HRMS (ES) calcd. for C17H17N3 (M þ H) 264.1500, found 264.1499.
2-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-yl)-1-phenyl-ethanone
This was prepared by the general method, using sec-BuLi (0.85 ml, 1.1 mmol,
1.3 M in cyclohexane), 3,4-dimethyl-5-phenyl-4H-[1,2,4]triazole (0.173 g,
1 mmol), TMEDA (0.66 ml, 4.4 mmol), methylbenzoate (0.15 ml, 1.2 mmol),
and dry THF (20 ml). The title compound was obtained as mauve
crystals, 0.18 g (63%). dH (400 MHz, CDCl3): 3.65 (3, s, CH3), 4.65 (2, s,
CH2), 7.50–7.56 (5, m, Ar-H), 7.63–7.68 (3, m, Ar-H), 8.14 (2, d,
J ¼ 7.6 Hz, Ar-H). Mp 144–1458C. HRMS (ES) calcd. for C17H15N3O
(M þ H) 278.1293, found 278.1292.
1-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylmethyl)-cyclohexanol
This was prepared by the general method, using sec-BuLi (0.85 ml, 1.1 mmol,
1.3 M in cyclohexane), 3,4-dimethyl-5-phenyl-4H-[1,2,4]triazole (0.173 g,
1 mmol), TMEDA (0.66 ml, 4.4 mmol), cyclohexanone (0.12 ml, 1.2 mmol),
and dry THF (20 ml). The title compound was obtained as light yellow
crystals, 60 mg (20%). dH (400 MHz, CDCl3): 1.26–1.37 (1, m, J ¼ 3.5 Hz,
OH), 1.51–1.82 (10, m, J ¼ 3.5 Hz, cyclohexyl), 2.92 (2, s, CH2), 3.63
(3, s, CH3), 7.50–7.53 (3, m, J ¼ 4.3 Hz, Ar-H), 7.62–7.65 (2, m,
J ¼ 3.8 Hz, Ar-H). Mp 182–1838C. HRMS (ES) calcd. for C16H21N3O
(M þ H) 272.1763, found 272.1769.

3-Aryl-5-methyl 4-Substituted [1,2,4]Triazoles
2227
4-Methyl-3-phenyl-5-phenylsulphanylmethyl-4H-[1,2,4]triazole
This was prepared by the general method, using sec-BuLi (0.85 ml, 1.1 mmol,
1.3 M in cyclohexane), 3,4-dimethyl-5-phenyl-4H-[1,2,4]triazole (0.173 g,
1 mmol), TMEDA (0.66 ml, 4.4 mmol), diphenyldisulphide (0.26 g,
1.2 mmol), and dry THF (20 ml). The title compound was obtained as white
crystals, 70 mg (25%). dH (400 MHz, CDCl3): 3.66 (3, s, CH3), 4.34 (2, s,
CH2), 7.25–7.33 (3, m, J ¼ 4.6 Hz, Ar-H), 7.43–7.45 (2, m, J ¼ 7.4 Hz,
Ar-H), 7.49–7.51 (3, m, J ¼ 4.7 Hz, Ar-H), 7.60–7.62 (2, m, J ¼ 3.5 Hz,
Ar-H). Mp 117–1188C. HRMS (ES) calcd. for C16H15N3S (M þ H)
282.1065, found 282.1069.
The disulphenylated derivative was also obtained as yellow crystals,
40 mg (11%). dH (400 MHz, CDCl3): 3.86 (3, s, CH3), 5.94 (1, s, CH),
7.30–7.32 (6, m, J ¼ 3.3 Hz, Ar-H), 7.42–7.45 (4, m, J ¼ 3.5 Hz, Ar-H),
7.50–7.53 (3, m, J ¼ 3.1 Hz, Ar-H), 7.57–7.59 (2, m, J ¼ 3.5 Hz, Ar-H).
HRMS (ES) calcd. for C22H19N3S2 (M þ H) 390.1098, found 390.1107.
(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylmethyl)-phosphoric Acid
Diethyl Ester
This was prepared by the general method, using sec-BuLi (0.79 ml, 1.1 mmol,
1.4 M in cyclohexane), 3,4-dimethyl-5-phenyl-4H-[1,2,4]triazole (0.173 g,
1 mmol), TMEDA (0.66 ml, 4.4 mmol), diethyl chlorophosphate (0.17 ml,
1.2 mmol), and dry THF (20 ml). The crude product was purified with prepara-
tive HPLC. The MeCN was removed in vacuo, and the remaining waterphase
was freeze-dried which gave the title compound as a colorless glassy
oil, 60 mg (20%). dH (400 MHz, MeOD): 1.33–1.36 (6, t, J ¼ 7.1 Hz,
(-CH2CH3)2), 1.93 (2, s, P-CH2-C), 3.74 (3, s, N-CH3), 7.58–7.60 (3, m,
J ¼ 2.5 Hz, Ar-H), 7.66–7.68 (2, m, J ¼ 2.3 Hz, Ar-H). HRMS (ES) calcd.
for C16H15N3 (M þ H) 309.1315, found 310.1324.
3-But-3-enyl-4-methyl-5-phenyl-4H-[1,2,4]triazole
This was prepared by the general method, using sec-BuLi (0.79 ml, 1.1 mmol,
1.4 M in cyclohexane), 3,4-dimethyl-5-phenyl-4H-[1,2,4]triazole (0.173 g,
1 mmol), TMEDA (0.66 ml, 4.4 mmol), allylbromide (0.10 ml, 1.2 mmol),
and dry THF (20 ml). The title compound was obtained as white crystals,
0.17 g (79%). dH (400 MHz, CDCl3): 2.64–2.66 (2, m, J ¼ 6.6 Hz, -CH2-),
2.89–2.93 (2, t, J ¼ 7.0 Hz, -CH2-), 3.61 (3, s, N-CH3), 5.07–5.10 (1, d,
J ¼ 10.1 Hz, 55CH2), 5.16 (1, d, J ¼ 16.9 Hz, 55CH2), 5.91–6.01 (1, m,
J ¼ 6.6 Hz, CH), 7.51–7.54 (3, m, Ar-H), 7.63 (2, m, Ar-H). Mp 156–
1588C. HRMS (ES) calcd. for C13H15N3 (M þ H) 214.1344, found 213.1347.

¨
J. Lindstrom and M. H. Johansson
2228
Dimethyl-[4-(4-methyl-5-phenethyl-4H-[1,2,4]
triazol-3-yl)phenyl]-amin
This was prepared by the general method, using sec-BuLi (0.79 ml, 1.1 mmol,
1.4 M in cyclohexane), [4-(4,5-dimethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-
dimethyl-amine (0.216 g, 1 mmol), TMEDA (0.66 ml, 4.4 mmol), and dry
THF (20 ml). Benzylbromide (0.14 ml, 1.2 mmol) was then added. The title
compound was obtained as yellow crystals, 0.23 g (75%). dH (400 MHz,
CDCl3): 3.02 [6, s, N-(CH3)2], 3.07–3.09 (2, t, J ¼ 8.1 Hz, CH2), 3.17–
3.19 (2, t, J ¼ 8.1 Hz, CH2), 3.29 (3, s, N-CH3), 6.77 (2, d, J ¼ 8.8 Hz,
Ar-H), 7.21–7.24 (3, m, J ¼ 6.8 Hz, Ar-H), 7.29–7.31 (2, m, J ¼ 7.3 Hz,
Ar-H), 7.44–7.46 (2, m, J ¼ 8.8 Hz, Ar-H). Mp 173–1748C. HRMS (ES)
calcd. for C19H22N4 (M þ H) 307.1922, found 307.1929.
ACKNOWLEDGMENTS
We thank David Wensbo and Johan Malmberg for helpful discussions and
Anna Risberg for technical assistance.
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