Efficient new approach for the synthesis of N,N-dialkylamino-1,2,4-triazoles

Article abstract of DOI:10.3987/COM-06-10886

A series of 3-NN-dialkylamino-4,5-diaryl-1,2,4-triazoles were synthesized in high yield under mild reaction conditions by coupling functionalized arylmagnesiums with isothiocyanates and cyclization with Viehe's salts. No selective thionation reaction was

Full text of DOI:10.3987/COM-06-10886

HETEROCYCLES, Vol. 68, No. 12, 2006
2635
HETEROCYCLES, Vol. 68, No. 12, 2006, pp. 2635 - 2645. © The Japan Institute of Heterocyclic Chemistry
Received, 14th September, 2006, Accepted, 30th October, 2006, Published online, 2nd November, 2006. COM-06-10886
EFFICIENT NEW APPROACH FOR THE SYNTHESIS OF
N,N-DIALKYLAMINO-1,2,4-TRIAZOLES
Qiang Zhang,*† Youyi Peng, and William J. Welsh*
Department of Pharmacology, Robert Wood Johnson Medical School, University
of Medicine & Dentistry of New Jersey (UMDNJ) & the Informatics Institute of
UMDNJ, 661 Hoes Lane, Piscataway, NJ 08854, Tel: 732-235-3234, Fax:
732-235-3475, Email: qzhang@intracellulartherapies.com, welshwj@umdnj.edu
†
Current address: Intra-Cellular Therapies, Inc., 3960 Broadway, NewYork,
NY10032
Abstract – A series of 3-N,N-dialkylamino-4,5-diaryl-1,2,4-triazoles were
synthesized in high yield under mild reaction conditions by coupling
functionalized arylmagnesiums with isothiocyanates and cyclization with Viehe's
salts. No selective thionation reaction was required for the preparation of
carbamoyl derivatives.
INTRODUCTION
The 1,2,4-triazoles are a large family of heterocyclic compounds, examples of which exhibit a wide range
of biological activities. They have been reported as novel glycogen synthase kinase-3 (GSK-3)
inhibitors,1
large-conductance
Ca2+
activated
potassium
channel
openers,2
and
anti-inflammatory/antipyretic agents with low acute toxicity.3 In our efforts to discover small-molecule
probes that target specific biological targets, an efficient method was achieved for the preparation of a
series of 3-N,N-dialkylamino-4,5-diaryl-1,2,4-triazole derivatives (Figure 1). Surprisingly, a search of the
literature on the subject revealed that these compounds have not been fully explored until recently.4-6 In
this paper, we describe an efficient method to synthesize 3-N,N-dialkylamino-4,5-diaryl-1,2,4-triazoles.

2636
HETEROCYCLES, Vol. 68, No. 12, 2006
Figure 1
N N
R1
R3
N
R2
R1, R2 = alkyl, aryl, R3 = N,N-dialkylamino
RESULTS AND DISCUSSION
Although many synthetic methods have been proposed for the preparation of trisubstituted 1,2,4- triazoles,
such as the Einhorn-Brunner reaction7 and the methods developed by Katritzky and Larson et al..8-12 In
most cases the reaction conditions are vigorous and the chemistry is not clean. Here, we report a new
approach for the synthesis of 3-(N,N-dialkylamino)-1,2,4-triazoles with few steps, mild conditions and
high yield. In our strategy, functionalized thioamides served as key intermediates in the synthesis of 1
(Scheme 1). Normally, thioamides are synthesized from amides with P4S10, Lawesson's reagent or
Scheme 1
N N
N
H2N N
HN
R1
R1
R3
R2
S
R2
3
1
R1
I/Br
NCS
HN
+
R1
R2
R2
2
2a: R1=3-CON(CH2CH3)2, R2=3-OCH3; 2b: R1=4-CON(CH2CH3)2, R2=3-OCH3;
2c: R1=3-C(CH3)3, R2=3-OCH3; 2d: R1=3-C(CH3)3, R2=4-OCH3;
2e: R1=3-C6H5, R2=3-OCH3; 2f: R1=4-C6H5, R2=4-OCH3
thionation reagent composed of P4S10 and siloxane.13,14 However, these methods require selective
thionation of amide functional groups in the synthesis of carbamoyl derivatives. In our synthesis, the

HETEROCYCLES, Vol. 68, No. 12, 2006
2637
thioamides were directly obtained by coupling arylmagnesiums with isothiocyanates. This reaction can be
conducted smoothly at room temperature in excellent yield. After exploring various procedures for
arylmagnesium preparation, Knochel's procedure15-18 of low-temperature iodine-magnesium exchange
was found the best way to prepare arylmagnesium reagents. This reaction is mild and occurs within 3
hours at 0°C in high yield. For thioamides (2a and 2b), the desired chemical selectivity was achieved
while the number of synthetic steps was minimized (Scheme 2).18,19
Scheme 2
O
O
O
C2H5
C2H5
i-propylMgCl
C2H5
C2H5
diethylamine
N
Cl
O
N
IMg
O
I
I
THF, -20-00C
CHCl3, 0 0C-rt, 97%
NCS
OCH3
THF, 0-200C, 95% (2 steps)
C2H5
N
C2H5
NH
S
N
IMg
C2H5
C2H5
H3CO
2a,2b
For 2c-2f, preliminary studies indicated an efficient synthesis of 3-tert-butylbenzoic acid is required, but
the separation of 3- and 4- isomers is tedious using literature methods.20 To overcome the difficulty in
purification, a concise synthesis of 3-tert-butyphenyl substituted thioamides is proposed here (Scheme 3).
Scheme 3
NH2
NH2
Br
Br
NBS
t-butyl nitrite
CHCl3, 0 0C-rt, 99%
DMF, 65-670C, 75%
4
5
S
NCS
MgBr
N
Mg
THF,rt-450C, 95%
OCH3
H
R2
THF,00C-rt, 99%
6
2c-2f
2-Bromo-4-tert-butylaniline (4) could be synthesized in nearly 100% yield by bromination of
4-tert-butylamine with N-bromosuccinimide (NBS) at 0°C. After diazonation and deamination reactions,

2638
HETEROCYCLES, Vol. 68, No. 12, 2006
the key intermediate 1-bromo-3-tert-butylbenzene (5) was obtained in 75% overall yield.21 The
corresponding magnesium reagent (6) was prepared without any difficulty under standard conditions.22
Moreover, all reactions developed here are mild and most of intermediates can be used for the subsequent
reaction without separation. With 2 in hand, the amidrazones were synthesized smoothly with excess
hydrazine in anhydrous alcohol in 100% yield, after which the final cyclization reaction was pursued.
Although 1 can be obtained by condensing amidrazone with carbamoyl chlorides or corresponding acids,7
the reaction condition is vigorous and the yield is not satisfactory. Therefore, phosgeniminium chlorides
(Viehe's salts) were used to complete the cyclization reaction.23-30 Viehe's salts are valuable synthons for
heterocyclic synthesis, notably because of their ability to dechloroalkylate.28 The reaction is extremely
mild and the cyclization can be finished within 5 hours (Table 1). Viehe's salts, which are stable for
weeks at room temperature, can be synthesized in a straightforward manner and used directly for
cyclization to yield triazoles with sufficiently high purity.31-34
Table 1: Synthesis of 3-N,N-dialkylamino-4,5-diaryl-1,2,4-triazoles (1)
H2N
R'
Cl
R'
Cl
N N
N
S
N
N
R1
R3
HN
HN
NH2NH2
R1
R1
EtOH, 0oC-rt
CH2Cl2, rt-reflux
R2
R2
R2
2
3
1
Total yield
(%)a
No.
R1
R2
R′
R3
1a
1b
1c
1d
3-CON(CH2CH3)2
4-CON(CH2CH3)2
3-C(CH3)3
3-OCH3
3-OCH3
3-OCH3
4-OCH3
-CH3
-CH3
-CH3
-CH3
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
79
76
81
81
3-C(CH3)3
H3C N
N
H3C N
O
1e
1f
3-C(CH3)3
3-C(CH3)3
3-OCH3
3-OCH3
72
73
O
N
1g
1h
3-C6H5
4-C6H5
3-OCH3
3-OCH3
-CH3
-CH3
N(CH3)2
N(CH3)2
76
74
a: isolated yield of analytically pure products from 2

HETEROCYCLES, Vol. 68, No. 12, 2006
2639
In summary, we have developed an efficient and practical method to synthesize
N,N-dialkylamino-1,2,4-triazoles under mild reaction conditions and in high overall yield, which can be
used for library synthesis and scale-up production.
EXPERIMENTAL
1H-NMR spectra were recorded at 400 MHz on Varian Gemini-400 spectrometer, in deuterated
chloroform (CDCl3) or DMSO (DMSO-d6) solution at room temperature, using TMS (0.00 ppm) as
13
internal standards and were reported in parts per million (ppm). C-NMR spectra were recorded on a
Varian Gemini 100 MHz NMR spectrometer at room temperature in CDCl3 and were internally
referenced to CDCl3 (77.23 ppm). Abbreviations for signal coupling are as follows: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; w, wide. Coupling constants, J, are reported (Hz). Analytical Thin
Layer Chromatography (TLC) was performed on pre-coated plastic backed plates purchased from
Aldrich (silica gel 60 F254; 0.25mm thickness). Flash column chromatography was conducted with silica
gel 60 (230-400 mesh) from Natland Co. MS and MS-MS were conducted on a Finnigan LCQ DUO
Mass Spectrum (Thermo Quest Co.). Gas chromatographic analyses were performed on a
Hewlett-Packard 6890 GC-MS instrument with a FID detector using 25 m × 0.20 mm capillary column
with cross-linked methylsiloxane as a stationary phase. Melting points were taken on a Mel-temp
melting point apparatus in open capillary tubes without calibration.
All reactions were carried out with anhydrous solvents in oven-dried and argon-charged glassware. All
anhydrous solvents except as mentioned were freshly distilled and stored in 4Å molecular sieves. All
solvents used in workup, extraction procedures, recrystallization process and chromatography were used
as received from commercial supplier without further purification. All reagents were purchased from
Aldrich Chemical Company.
General procedure for the synthesis of thioamides ( 2a-2f ):
a: arylmagnesium preparation:
A 50ml three-necked flask containing THF (15mL) was flushed with argon, and iodide compound (13.6
mmol) was added in one portion. The solution was cooled to -20°C. Isopropylmagnesium chloride (1.0 M
in THF, 1.05 equiv.) was dropped into the iodide solution via syringe. The yellow solution was stirred at
-20°C for 30 min and warmed to rt.
For 2c and 2d arylmagnesium preparation, a 50mL three-necked flask containing THF (15mL) was
flushed with argon. Bromide (13.6 mmol) was dissolved in THF and magnesium (0.39 g, 1.2 equiv.) was
added in one portion. After a piece of iodine was added, the flask was immersed in 40-50°C water bath
without stirring. The reaction took place within 10 min and the mixture was cloudy. The solution was
stirred until clear (some magnesium remained). The flask was removed from the bath to cool to rt.

2640
HETEROCYCLES, Vol. 68, No. 12, 2006
b: coupling with isothiocyanate
Isothiocyanate (1.0 equiv.) was dropped into above arylmagnesium solution slowly under vigorous
stirring. The coupling reaction took place immediately and the solution color changed to brown. Following
this procedure, the solution was stirred at rt for 2 h. The reaction was quenched by adding saturated
aqueous NH4Cl solution. Solid was filtered and the organic solution was extracted by water (2 × 20mL)
and the combined organic layers were dried with MgSO4. After solvent evaporation, the residue was
purified by recrystallization or flash chromatography using a mixture of hexane and EtOAc as eluent.
N,N-Diethyl-3-(3-methoxyphenylcarbamothioyl)benzamide (2a): yellow syrup, yield 98%. TLC
1
(EtOAc:hexane = 3:20 ), Rf = 0.35. H-NMR (400 MHz, CDCl3) δ1.09 (s, 3H), 1.18 (t, J = 8.2 Hz,
3H),3.21 (d, J = 6.1 Hz, 2H), 3.47 (d, J = 7.5 Hz, 2H), 3.81 (s, 3 H), 6.81(d, J = 7.4 Hz, 1H), 7.25-7.37
(m, 4 H), 7.65 (d, J = 6.2 Hz, 2H), 7.80 (d, J = 7.5 Hz, 1H ), 10.48 (s, 1 H). 13C-NMR (100 MHz, CDCl3)
δ170.5, 159.9, 143.4, 140.5, 130.9, 129.6, 128.6, 128.4, 128.3, 124.4, 115.8, 112.7, 109.1, 55.9, 43.5, 39.5.
MS (ESI) = 313.4 (M++1).Anal. Calcd for C19H22N2O2S: C 66.64, H 6.48, N 8.18, O 9.34, S 9.36. Found:
C 66.59, H 6.49, N 8.20, O 9.33, S 9.35.
N,N-Diethyl-4-(3-methoxyphenylcarbamothioyl)benzamide (2b): yellow solid, yield 96%. TLC
1
(EtOAc:hexane = 3:20), Rf = 0.35, mp 85-87°C. H-NMR (400 MHz, CDCl3) δ1.05 (t, J = 7.2 Hz, 3H),
1.16 (t, J = 6.4 Hz, 3H ), 3.17 (d, J = 7.5 Hz, 2H), 3.45 (d, J = 7.5 Hz, 2H), 3.82 (s, 3 H), 6.82 (d, J = 7
Hz, 1H), 7.11(d, J = 8 Hz, 2H), 7.31(t, J = 8 Hz, 1H), 7.39 (d, J = 7 Hz, 1H), 7.66 (s, 1 H), 7.76 (d, J = 8
13
Hz, 2H), 10.62 (s,1 H). C-NMR (100 MHz, CDCl3) δ170.7, 159.8, 143.5, 140.6, 138.5, 131.2, 129.4,
127.5, 125.9, 116.2, 112.6, 109.6, 55.4, 43.8, 39.5. MS (ESI) = 313.4 (M++1). Anal. Calcd for
C19H22N2O2S: C 66.64, H 6.48, N 8.18, O 9.34, S 9.36. Found: C 66.63, H 6.47, N 8.19, O 9.38, S 9.38.
3-tert-Butyl-N-(3-methoxyphenyl)benzothioamide (2c): yellow solid, yield 93%. TLC (EtOAc:hexane
1
= 1:4), Rf = 0.32, mp 106-108°C. H-NMR (400 MHz, CDCl3) δ1.36 (s,9 H), 3.83 (s,3 H ), 6.84 (d, J =
7.2 Hz, 1H), 7.24 (s,1 H), 7.34 (d, J = 8.0 Hz, 2H), 7.55 (m, 3 H), 7.86 (s, 1 H), 8.95 (s,1 H). 13C-NMR
(100 MHz, CDCl3) δ 160.0, 152.3, 142.9, 140.2, 134.5, 129.7, 128.5, 128.3, 124.1, 123.4, 115.6, 112.7,
109.2, 55.4, 34.9, 31.3. MS (ESI) = 300.3(M++1). Anal. Calcd for C18H21NOS: C 72.70, H 7.07, N 4.68,
O 5.34, S 10.71. Found: C 72.73, H 7.05, N 4.67, O 5.36, S 10.70.
3-tert-Butyl-N-(4-methoxyphenyl)benzothioamide (2d): yellow solid, yield 95%. TLC (EtOAc:hexane
= 1:4), Rf = 0.32, mp 93-95°C. 1H-NMR (400 MHz, CDCl3) δ1.37 (s, 9 H), 3.84 (s,3 H ),6.97 (d, J = 7.5
Hz, 2H), 7.37 (t, J = 6.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.5 Hz, 3H), 7.88 (s, 1 H), 8.89 (s,1
13
H). C-NMR (100 MHz, CDCl3) δ 158.2, 151.8, 142.9, 132.1, 130.3, 128.5, 128.3, 127.7, 124.1, 123.5,
122.8, 114.2, 55.5, 35.1, 31.3. MS (ESI) = 300.3 (M++1). Anal. Calcd for C18H21NOS: C 72.70, H 7.07, N
4.68, O 5.34, S 10.71. Found: C 72.71, H 7.08, N 4.68, O 5.35, S 10.69
N-Phenylbiphenyl-3-carbothioamide (2e): yellow syrup, yield 92%. TLC (EtOAc:hexane = 1:3), Rf =

HETEROCYCLES, Vol. 68, No. 12, 2006
2641
0.28. 1H-NMR (400 MHz, CDCl3) δ 3.84 (s,3 H), 6.84(d, J = 8.2 Hz, 1H), 7.28-7.78 (m, 11 H), 8.03 (s, 1
13
H), 9.04 (s,1 H). C-NMR (100 MHz, CDCl3) δ 160.0, 140.1, 140.1, 130.9, 129.9, 129.8, 129.1, 128.9,
128.8, 127.8, 127.4, 127.1, 125.6, 125.4, 115.6, 112.7, 109.0, 55.5. MS (ESI) = 320.3(M++1). Anal. Calcd
for C19H15NS: C 78.86, H 5.22, N 4.84, S 11.08. Found: C 78.88, H 5.20, N 4.83, S 11.06.
N-Phenylbiphenyl-4-carbothioamide (2f): yellow solid, yield 92%. TLC (EtOAc:hexane = 1:3), Rf =
0.28. mp 112-114°C. 1H-NMR (400 MHz, CDCl3 ) δ 3.84 (s, 3 H), 6.84 (d, J = 8.2 Hz, 1H), 7.28-7.78 (m,
13
11 H), 8.03 (s, 1 H), 9.04 (s, 1 H). C-NMR (100 MHz, CDCl3) δ 160.4, 140.2, 139.8, 129.8, 128.9,
128.1, 127.2, 127.1, 115.7, 112.8, 109.1, 55.4. MS (ESI) = 320.3 (M++1). Anal. Calcd for C19H15NS: C
78.86, H 5.22, N 4.84, S 11.08. Found: C 78.83, H 5.25, N 4.80, S 11.09
General procedure to synthesize 1a-1f
In a 50 ml three-necked flask, thioamide (6.6 mmol) was suspended in anhydrous EtOH (60mL) and
cooled to 0°C. Anhydrous hydrazine (2 mL, 10 equiv.) was dropped in slowly under vigorous stirring,
while the temperature was kept under 0°C. Afterwards the flask was brought to rt and stirred for 5h at rt.
TLC indicated the reaction was finished and EtOH and hydrazine were evaporated under high vacuum.
The residue dissolved in CHCl3 (30 mL) and extracted by water (3 × 20 mL). After drying by MgSO4, the
CHCl3 was evaporated and amidrazone was dried overnight under vacuum before it was used for next
step.
To a 50 ml three-necked flask which contained CH2Cl2 (10 mL), Viehe's salt (2.7mmol) was added
quickly in one portion under stirring. 5 min later, amidrazone (0.9 equiv.) was added slowly. After
stirring for 30 min at rt, the reaction was heated to reflux overnight. TLC indicated the reaction usually
finished within 5 h. The mixture was cooled to rt and the organic solution was extracted by water; the
organic layer was dried by MgSO4 and concentrated. The triazoles were purified by flash chromatography
by using CHCl3 and MeOH or EtOAc and hexane as eluent.
3-(5-(Dimethylamino)-4-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-N,N-diethylbenzamide (1a): white
solid, yield 81%. TLC (CHCl3: MeOH = 20:1), Rf = 0.35, mp112-114°C. 1H-NMR (400 MHz, CDCl3) δ
1.37 (s, 9 H), 3.84 (s, 3 H ),6.97 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 2.6 Hz, 1H), 7.53 (d, J = 8.0Hz, 1H), 7.63
13
(t, J = 7.0 Hz, 3H), 7.88 (s, 1H), 8.89(s,1H). C-NMR (100 MHz, CDCl3) δ 170.2, 160.6, 159.6, 151.4,
137.3, 136.1, 136.0, 130.6, 129.0, 128.6, 128.5, 127.8, 127.3, 126.5, 119.7, 114.9, 113.2, 55.5, 41.4, 39.2.
MS(ESI) = 394.4 (M++1). Anal. Calcd for C19H15NS: C 78.86, H 5.22, N 4.84, S 11.08. Found: C 78.83,
H 5.25, N 4.80, S 11.09.
4-(5-(Dimethylamino)-4-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-N,N-diethylbenzamide
(1b):
1
white solid, yield 79%. TLC (CHCl3: MeOH = 20:1), Rf = 0.35, mp144-145°C. H-NMR (400 MHz,
DMSO-d6) δ1.00 (s, 3 H), 2.64 (s, 6 H ),3.11 (s, 2 H), 3.40 (s, 2 H), 3.73 (s, 3 H), 6.96 (d, J = 6.5 Hz, 1
H), 7.04 (s, 1 H), 7.08 (d, J = 6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 5.0 Hz, 2 H), 7.43 (t, J =

2642
HETEROCYCLES, Vol. 68, No. 12, 2006
13
8.0 Hz, 1H). C-NMR (100 MHz, CDCl3) δ 170. 5, 160.6, 159.8, 151.5, 137.8, 135.9, 130.7, 128.6,
128.4, 126.2, 119.7, 114.7, 113.3, 55.5, 43.2, 41.4, 39.3. MS (ESI) = 394.3 (M++1). Anal. Calcd for
C19H15NS: C 78.86, H 5.22, N 4.84, S 11.08. Found: C 78.85, H 5.26, N 4.85, S 11.06.
5-(3-tert-Butylphenyl)-4-(3-methoxyphenyl)-N,N-dimethyl-4H-1,2,4-triazol-3-amine (1c): white
1
crystal, yield 87%. TLC (EtOAc:hexane=1:2), Rf = 0.61, mp120-122°C. H-NMR (400 MHz, CDCl3)
δ1.12 (s, 9 H), 2.73 (s, 6 H ), 3.73 (s, 3 H), 6.74 (t, J = 2.5 Hz, 1 H), 6.84 (d, J = 6.2 Hz, 1 H), 6.95 (dd, J1
= 2.0 Hz, J2 = 4.0Hz 1 H), 7.18-7.20 (m, 1 H), 7.22 (s, 0.5 H), 7.28 (tt, J1 = 2.0 Hz, J2 = 5.0Hz, 2 H),
7.32(s, 0.5 H), 7.34 (s, 0.5 H), 7.36 (s, 0.5 H). 13C-NMR (100 MHz, CDCl3) δ 160.5, 159.4, 152.5, 150.7,
136.4, 130.5, 128.0, 127.7, 126.1, 125.9, 125.8, 119.8, 114.6, 113.3, 55.5, 41.5, 34.5, 31.0. MS (ESI) =
351.3 (M++1). Anal. Calcd for C21H26N4O: C 71.97, H 7.48, N 15.99, O 4.57. Found: C 71.99, H 7.45, N
16.01, O 4.54.
5-(3-tert-Butylphenyl)-4-(4-methoxyphenyl)-N,N-dimethyl-4H-1,2,4-triazol-3-amine (1d): white
1
crystal, yield 85%. TLC (EtOAc:hexane = 1:2), Rf = 0.61, mp118-120°C. H-NMR (400 MHz, CDCl3)
δ1.14 (s,9 H), 2.75 (s, 6 H ), 3.82 (s, 3 H), 6.93 (d, J = 5.3 Hz, 2 H), 7.16 (d, J = 5.5 Hz, 2 H), 7.17-7.22
13
(m, 3 H), 7.32 (d, J = 2.0 Hz, 1H). C-NMR (100 MHz, CDCl3) δ 159.8, 159.7, 152.7, 150.8, 128.7,
128.0, 127.2, 126.0, 125.9, 125.8, 115.0, 114.9, 55.6, 41.5, 34.5, 31.0. MS (ESI) = 351.3 (M++1). Anal.
Calcd for C21H26N4O: C 71.97, H 7.48, N 15.99, O 4.57. Found: C 72.01, H 7.50, N 15.97, O 4.56.
1-(5(3-tert-Butylphenyl)-4-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-4-methylpiperazine (1e): white
1
solid, yield 78%. TLC (EtOAc:hexane = 1:2), Rf = 0.43, mp164-166°C. H-NMR (400 MHz, CDCl3)
δ1.12 (s, 9 H), 2.30 (s, 3 H ), 2.38 (d, J = 5.0 Hz, 2H), 3.14(t, J=5Hz, 2H), 3.75(s, 3H), 6.74(t, J = 2Hz,
1H), 6.83(d, J = 1Hz, 1 H), 6.95(dd, J1 = 2.0 Hz, J2 = 6.0 Hz, 1 H), 7.19-7.27 (m, 3 H), 7.33 (t, J1 = 5.0Hz,
J2 = 6.2 Hz, 2 H). 13C-NMR (100 MHz, CDCl3) δ 160.5, 158.0, 152.6, 150.8, 136.1, 130.6, 130.5, 128.1,
126.9, 126.2, 125.9, 119.2, 114.8, 112.7, 55.5, 54.4, 49.1, 46.1, 34.5, 31.0. MS (ESI) = 406.5 (M++1).
Anal. Calcd for C24H31N5O: C 71.08, H 7.70, N 17.27, O 3.95. Found: C 71.12, H 7.65, N 17.30, O 3.98.
4-(5(3-tert-Butylphenyl)-4-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)morpholine (1f): white crystal,
yield 79%. TLC (EtOAc:hexane = 1:2), Rf = 0.51, mp155-156°C. 1H-NMR (400 MHz, CDCl3) δ1.12 (s, 9
H), 2.14 (t, J = 5.0 Hz, 2 H), 3.65 (t, J = 5.0 Hz, 2 H), 3.74 (S, 3 H), 6.78 (S, 1 H), 6.86 (d, J = 7.0 Hz, 1
H), 6.97 (dd, J1 =2.0 Hz, J2 = 6.4 Hz, 1 H), 7.21-7.28 (m, 3 H), 7.35 (t, J = 5.6 Hz, 2 H). 13C-NMR (100
MHz, CDCl3) δ 160.7, 157.2, 152.5, 151.0, 153.6, 130.7, 128.2, 126.6, 126.1, 126.0, 125.9, 119.2, 115.1,
112.9, 66.2, 55.6, 49.4, 34.5, 31.0. MS (ESI) = 393.5 (M++1). Anal. Calcd for C23H28N4O2: C 70.38, H
7.19, N 14.27, O 8.15. Found: C 70.35, H 7.22, N 14.30, O 8.11.
5-(Biphenyl-3-yl)-4-(3-methoxyphenyl)-N,N-dimethyl-4H-1,2,4-triazol-3-amine (1g): white solid,
1
yield 83%. TLC (ethyl acetate:hexane = 1:2), Rf = 0.57, mp116-118°C. H-NMR (400 MHz, CDCl3) δ
2.75 (s, 6 H), 3.76 (s, 3 H), 6.81(t, J = 2.0 Hz, 1 H), 6.87 (d, J = 1.0 Hz, 2 H), 7.01 (dd, J1= 1.0 Hz, J2=

HETEROCYCLES, Vol. 68, No. 12, 2006
2643
5.4 Hz, 1 H), 7.29-7.40 (m, 8 H), 7.51-7.54 (m, 2 H). 13C-NMR (100 MHz, CDCl3) δ 160.6, 159.3, 152.0,
141.0, 140.3, 136.4, 130.6, 128.7, 128.7, 128.0, 127.8, 127.5, 127.4, 127.3, 127.0, 119.9, 114.7, 113.4,
55.6, 41.5. MS (ESI) = 371.3 (M++1). Anal. Calcd for C23H22N4O: C 74.57, H 5.99, N 15.12, O 4.32.
Found: C 74.56, H 6.02, N 15.11, O 4.30.
5-(Biphenyl-4-yl)-4-(3-methoxyphenyl)-N,N-dimethyl-4H-1,2,4-triazol-3-amine (1h): white solid,
yield 81%. TLC (EtOAc:hexane = 1:2), Rf = 0.56, mp126-128°C. 1H-NMR (400 MHz, CDCl3) δ 2.77 (s,
6 H ), 3.76 (s, 3 H), 6.85 (t, J1 = 2.5 Hz, J2 = 5.0 Hz , 2 H), 6.99 (d, J = 1.2 Hz, 1 H), 7.34 (t, J = 7 Hz, 1
H), 7.40-7.49 (m, 5 H), 7.67 (t, J1 = 7.2 Hz, J2 = 9.0 Hz, 2 H), 7.77(d, J = 8.0 Hz, 1 H), 7.83 (m, 1 H).
13C-NMR (100 MHz, CDCl3) δ 160.6, 159.5, 152.0, 136.2, 130.6, 128.8, 128.5, 127.8, 127.7, 127.6,
127.0, 126.3, 125.5, 119.8, 114.8, 113.4, 55.6, 41.5. MS (ESI) = 371.3 (M++1). Anal. Calcd for
C23H22N4O: C 74.57, H 5.99, N 15.12, O 4.32. Found: C 74.58, H 5.97, N 15.09, O 4.31.
ACKNOWLEDGEMENTS
The financial support from the Biotechnology Research and Development Corporation (BRDC, Peoria,
IL) for this research is gratefully acknowledged.
REFERENCES AND NOTES
1. P. H. Olesen, A. R. Sorensen, B. Urso, P. Kurtzhals, A. N. Bowler, U. Ehrbar, and B. F. Hansenet, J.
Med. Chem., 2003, 46, 3333.
2. J. L. Romine, S. W. Martin, V. K. Gribkoff, C. G. Boissard, S. I. Dworetzky, J. Natale, Y. Li, Q.
Gao, N. A. Meanwell, and J. E. Starrett Jr., J. Med. Chem., 2002, 45, 2942.
3. G. Grossi, M. D. Braccio, G. Roma, V. Ballabeni, M. Tognolini, F. Calcina, and E. Barocelli, Eur. J.
Med. Chem., 2002, 37, 933.
4. G. Roma, M. D. Braccio, G. Grossi, F. Mattioli, and M. Ghia, Eur. J. Chem., 2000, 35, 1021.
5. J. M. Quintela, M. J. Moreira, and C. Peinador, Trtrahedron, 1996, 52, 3037.
6. J. B. Hester, J. H. Ludens, D. E. Emmert, and B. E. West, J. Med. Chem., 1989, 32, 1157.
7. C. J. Temple, 'Triazoles, 1,2,4', John Wiley & Sons, Inc., 1981, pp.1-241.
8. A. B. Einhorn, T. Mauermayer, G. Schupps, and B. Szelinski, Justus Liebigs Ann. Chem., 1905, 343,
207.
9. A. R. Katritzky, V. Y. Vvedensky, K. Kovalenko, P. J. Steel, V. I. Markov, and B. Forood,
Synthesis, 2001, 897.
10. S. D. Larsen and B. A. DiPaolo, Org. Lett., 2001, 3, 3341.
11. H. H. Fahmy, A. El-masry, and A. Abdelwahed, Arch. Pharm. Res., 2001, 24, 27.

2644
HETEROCYCLES, Vol. 68, No. 12, 2006
12. P. Passaniti, W. R. Browne, F. C. Lynch, D. Hughes, M. Nieuwenhuyzen, P. James, M. Maestri, and
J. G. Vos, J. Chem. Soc., Dalton Trans., 2002, 1740.
13. P. Metzner and A. Thuillier, 'Sulfur Reagents in Organic Synthesis', Academic Press Inc., 1994, pp.
44-46.
14. T. J. Curphey, J. Org. Chem., 2002, 67, 6461.
15. G. Varchi, A. E. Jensen, W. Dohle, A. Ricci, G. Cahiez, and P. Knochel, Synlett, 2001, 477.
16. T. Delacroix, L. Berillon, G. Cahiez, and P. Knochel, J. Org. Chem., 2000, 65, 8108.
17. M. Abarbri, J. Thibonnet, L. Berillon, F. Dehmel, M. Rottlander, and P. Knochel, J. Org. Chem.,
2000, 65, 4618.
18. W. Dohle, D. M. Lindsay, and P. Knochel, Org. Lett., 2001, 3, 2871.
19. m- And p-iodo-N,N-diethylbenzamides were synthesized from p- and m-iodobenzoyl chlorides with
diethylamine in chloroform. The amides were used directly for next step without further purification.
20. S. J. Yu, A. C. Nail, and W. J. Welsh, unpublished data.
21. Procedure for the synthesis of 1-bromo-3-tert-butylbenzene: p-tert-butylaniline (8.5mL, 50.7 mmol)
was dissolved in CHCl3 (200 mL) and cool to 0 oC. NBS (9.03g, 1.0 equiv.) was added slowly under
o
vigrous stirring to control the temperature <3 C, and the brown solution was stirred at rt for 5 h.
GC-MS indicated >99% product was the desired 2-bromo-4-tert-butylaniline. The CHCl3 solution
was extracted by water (3×50 mL) and concentrated to use directly for next step. tert-Butyl nitrite
o
(10 mL, 1.5 equiv.) was dropped into DMF (30 mL) and the solution was stirred at 65-67 C, to
which 4-tert-butyl-2-bromoaniline (50 mmol) was added carefully. The black solution was stirred at
o
65 C for over night. The product was purified by flash chromatography to obtain 1-bromo-3-tert-
butylbenzene (8.0 g, 75%) as light yellow liquid. The structure was confirmed by GC-MS and NMR.
22. M. Schlosser, 'Organometallics in Synthesis', 2nd ed.; John Wiley & Sons, 2002, pp.1-352.
23. H. Bohme and H. G. Viehe, Iminium Salts in Organic Chemistry, 'Advances in Organic Chemistry',
John Wiley & Sons, 1976, pp. 342-419.
24. B. LeClef, J. Mommaerts, B. Stelander, and H. G. Viehe, Angew. Chem., Int. Ed. Engl., 1973, 12, 404.
25. F. Hervens and H. G. Viehe, Angew. Chem., Int. Ed. Engl., 1973, 12, 405.
26. C. Derycke, V. Jager, J. P. Putzeys, M. V. Meerssche, and H. G. Viehe, Angew. Chem., Int. Ed. Engl.,
1973, 12, 406.
27. J. Morris, D. G. Wishika, and Y. Fang, J. Org. Chem., 1992, 57, 6502.
28. N. Guilota, H. G. Viehe, B. Tinant, and J. P. Declercq, Tetrahedron, 1990, 46, 3897.
29. A. S. Kiselyov, Tetrahedron Lett., 2005, 46, 1177.
30. A. S. Kiselyov, Tetrahedron Lett., 2006, 47, 1395.
31. M. Vilkas and D. Qasmi, Synth. Commun., 1990, 20, 2769.

HETEROCYCLES, Vol. 68, No. 12, 2006
2645
32. Q. Song, Z. Wang, and Y. S. Sanghvi, Nucleosides, Nucleotides & Nucleic Acids, 2003, 22, 629.
33. R. N. Salvatore, S. Sahab, and K. W. Jung, Tetrahedron Lett., 2001, 42, 2055.
34. Q. Zhang, S. M. Keenan,Y. Peng, A. C. Nair, S. Yu, R. D. Howells, and W. J. Welsh, J. Med. Chem.,
2006, 49, 4044.