Synthesis of N,N-Disubstituted 3-amino- 1,2,4-triazoles

Article abstract of DOI:10.1055/s-2001-13400

A general method for the synthesis of N,N-disubstituted 3-amino-l,2,4-triazoles 5 from di(benzotriazolyl)methanimines 1 and 1′, hydrazine and substituted hydrazines is developed. The desired compounds were prepared regioselectively under mild conditions b

Full text of DOI:10.1055/s-2001-13400

PAPER
897
Synthesis of N,N-Disubstituted 3-Amino-1,2,4-triazoles
a
a,d
a
a,b
c
Alan R. Katritzky,* Boris V. Rogovoy, Vladimir Y. Vvedensky, Katherine Kovalenko, Peter J. Steel, Victor I.
d
e
Markov, Behrouz Forood
a
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611–7200, USA
Fax +1(352)3929199; E-mail: katritzky@chem.ufl.edu
b
c
d
e
A. E. Arbuzov Institute of Organic and Physical Chemistry, Arbuzov str. 8, Kazan 420088, Russia
Department of Chemistry, University of Canterbury, Christchurch 1, New Zealand
Ukrainian State Chemical Technology University (USChTU), Gagarina 8, Dniepropetrovsk, 49005, Ukraine
Exploratory Chemistry, Trega Biosciences, Inc., 9880 Campus Point Drive, San Diego, CA 92121, USA
Received 15 September 2000; revised 3 January 2001
the previously known methods do not allow the direct
synthesis of triazoles 5 bearing a substituted 3-amino
group; however, reaction of 1-benzoyl-S-methylisothi-
Abstract: A general method for the synthesis of N,N-disubstituted
3
-amino-1,2,4-triazoles 5 from di(benzotriazolyl)methanimines 1
and 1 , hydrazine and substituted hydrazines is developed. The de-
sired compounds were prepared regioselectively under mild condi- osemicarbazide with dimethylamine in a sealed tube at
tions by simple procedures in yields of up to 95%.
100 °C leads to 3-dimethylamino-5-phenyl-1,2,4-triazole
53%) accompanied by 2-amino-5-phenyl-1,3,4-oxadiaz-
(
Key words: acylation, cyclization, regioselectivity, triazoles, ben-
zotriazole, hydrazines
9c
ole and 3-methylthio-5-phenyl-1,2,4-triazole. 3-Mono-
substituted-amino-1,2,4-triazoles can be prepared by
reductive amination of unsubstituted analogs.9 3(5)-
Dimethylamino-1,2,4-triazole was prepared from dimeth-
ylcyanamide and formyl hydrazine at 140 °C.9
d,e
Aminotriazole derivatives are well known to be biologi-
f
cally active: 3-amino-1,2,4-triazole inhibits the synthesis
1
of catalase, a major detoxification enzyme against active Now we report a regiospecific, mild and convenient syn-
oxygen species, such as hydrogen peroxides. 3-Amino- thesis of 3-(N,N-disubstituted)amino-5-substituted-1H-
1
,2,4-triazole was also used as an inhibitor of histidine 1,2,4-triazoles and 3-(N,N-disubstituted)amino-1,5-dis-
2
biosynthesis in the cloning of arg1 gene. Several 3-ami- ubstituted-1H-1,2,4-triazoles.
notriazole derivatives are effective in eosinophilia models
Recently we reported a convenient method for the prepa-
3
for the treatment of chronic bronchial asthma. Benzopy-
rans with triazolylamino substituents were patented as
potassium channel activators for the treatment of disor-
ration of benzotriazole-1-carboximidamides 2 from
di(benzotriazolyl)methanimine 1 and various primary and
4
10a
secondary amines. Two examples suggested that com-
ders associated with smooth muscle contraction. Sufoti-
pounds 2 could easily be transformed into acyl derivatives
5
dine bismuth citrate, an aminotriazole, is a histamine H -
10a
2
3
, promising precursors for the synthesis of triazoles 5.
receptor antagonist which is used in the treatment of
duodenal and gastric ulceration and other conditions
where histamine is a known mediator. 3-Amino-1,2,4-tri-
We have now prepared further acyl derivatives 3a–g
(
(
Scheme 1, Table 1) and reacted them with hydrazines
Scheme 2).
6
azoles were also evaluated for herbicide activity.
Cyclization of acyl derivatives 3a–g with unsubstituted,
methyl, phenyl and benzyl hydrazines lead to the desired
Most previously described syntheses of the 1,5-disubsti-
tuted-3-amino-1,2,4-triazoles 5 are based on reactions of
3
-amino-1,2,4-triazoles 5a–k (Scheme 2, Table 2). Al-
7
a,b
aminoguanidines with carboxylic acids. An enhanced
synthetic route utilizing reactions of aminoguanidine with
though reaction of 3 with substituted hydrazines could
7c
methyl benzoates was developed by Mullican et al. to
synthesize 3-amino-5-aryl-1,2,4-triazoles under relatively
mild conditions (reflux in MeOH, 18 h) in high yields.
Arylcarbohydrazides are transformed into 2-aroyl-1-hy-
drazinecarboximidamides and cyclized in a sealed tube at
NH
NH
N
BrCN
2
N
Bt1
Bt1
1
2
+
Bt
Bt
N
65 %
H
1
1'
7
d
2
20 °C. Aminoguanidine smoothly reacts with ketones
O
to form hydrazones: cyclization of these derivatives al-
lows variation of the substituents at 1-nitrogen of the
O
NH
R3
Bt1
N
H
N
R1
R1
R2
R3
R1
Bt1
Cl
N
R2
2a-d
N
R2
7
e
1
,2,4-triazole ring. Less general synthetic routes to tria-
1+1'
THF
r.t.
8
TEA, THF
r.t.
zoles 5 are reactions of amidrazones with carbodiimides
3a-g
9
a,b
and of N-cyanoazomethines with hydrazines. Most of
1
2
N
N
Bt =
N
N
Bt =
Synthesis 2001, No. 6, 04 05 2001. Article Identifier:
N
N
1
©
437-210X,E;2001,0,06,0897,0903,ftx,en;M02300SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
Scheme 1

8
98
A. R. Katritzky et al.
PAPER
Table 1 Preparation of Acyl Derivatives of Benzotriazole-1-carboximidamides 3a–g
Entry
Compound 2 Compound 3 R1
R2
R3
Yield of
Compound 3 (%)
1
2
3
4
5
6
7
2a
2b
2c
2c
2c
2d
2c
3a
3b
3c
3d
3e
3f
C H
C H
(CH ) C
62
74
94
93
64
83
91
2
5
2
5
3 3
Allyl
Allyl
-(CH ) O(CH ) -
C H
6
5
Naphthalen-1-yl
C H
2
2
2 2
-(CH ) O(CH ) -
2
2
2 2
6
5
-(CH ) O(CH ) -
Thiophen-2-yl
C H
2
2
2 2
CH(CH3)2
CH(CH3)2
6
5
5
3g
-(CH ) O(CH ) -
C H
2
2
2 2
2
4
lead to mixtures of 3-amino-5-substituted and 3-substitut- ter of the substituent R of the hydrazine, the more of the
ed-5-amino isomers, the final products were obtained as side product 6b,e,f,j is formed (Scheme 2, Table 2). How-
single isomers 5a–k (Scheme 2).
ever, more experiments are needed to completely rational-
4
ize the influence of the R group. The nature of the
The position of the substituents was confirmed by X-ray
crystallography for compound 5g (Figure, Tables 3, 4)
and other structures were assigned by analogy and by
spectral comparison.
1
3
substituents R -R in the amino and acyl groups seems not
to affect the yield and selectivity of the cyclization. In
analogy to similar known reactions, competitive displace-
ment of the dialkylamino group rather then benzotriazole
moiety in the reaction of 3a,c,e,f with phenyl and benzyl-
hydrazine is unexpected. Indeed, selective substitution of
the benzotriazole moiety rather than the dialkylamino
group in the reaction of compounds of the type
The analysis of structure 5g suggests the following mech-
anism of the cyclization reaction: first, the unsubstituted
nitrogen atom in the hydrazine displaces the benzotriaz-
olyl moiety, and then cyclization at the carbonyl group in
the acyl fragment takes place (Scheme 2).
1
2
R NC=(O,NH)Bt with amines R NH proceeds with the
2
1
Phenyl and benzyl hydrazine, in contrast to unsubstituted formation of the derivatives R NC=(O,NH)NR and no
hydrazine and methylhydrazine, react with acyl deriva- symmetrical product is formed.
2
2
1
0
tives 3a,c,e,f with the competitive formation of 3-amino-
An attempt to synthesize compound 6k by reacting 1, 1’
with benzoic hydrazide gave only oxadiazole 7 in quanti-
tative yield (Scheme 3).
triazoles 5b,e,f,j and 3-Bt-substituted triazoles 6b,e,f,j (Bt
benzotriazole). The lower the electron-donating charac-
=
In summary, we have developed a general procedure for
the preparation of 3-(N,N-disubstituted)amino-5-substi-
tuted-1,2,4-triazoles 5a–k utilizing di(benzotriazolyl)-
methanimines 1 and 1 as intermediates. The reaction se-
quence was performed under mild conditions with simple
purification of the intermediates and final products.
Bt1
O
R1
N
N
R3
R2
3
a-g
H2N NHR4
4
O
N
R3
Bt1
O
N
H
N
H
N
+
R4
R1
R4
R3
N
N
N
H
R2
R1
Bt1
N
N
N
R3
R2
R3
+
N
N
N
N
R4
R4
5
a-k
6b,e,f,j
Figure Perspective view and atom labeling of one of the two inde-
pendent molecules in the X-ray crystal structure of 5g
Scheme 2
Synthesis 2001, No. 6, 897–903 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of N,N-Disubstituted 3-Amino-1,2,4-triazoles
899
able 2 Preparation of 3-(N,N-Dialkyl)amino-1,2,4-triazoles 5a–k
+
6
3
R1
R2
R3
R4
Yield of
Compound 5 Compound 6 (%)
%)
Yield of
(
3
3
3
3
3
3
3
3
3
3
3
a
a
b
b
c
c
c
e
f
C H
C H
(CH ) C
CH3
75
36
72
84
90
45
82
42
95
25
84
0
2
5
5
2
5
5
3 3
C H
C H
(CH ) C
C H CH
30
0
2
2
3 3
6
5
2
Allyl
Allyl
Allyl
Allyl
C H
H
6
5
5
C H
CH3
CH3
0
6
-(CH ) O(CH ) -
Naphthalen-1-yl
Naphthalen-1-yl
C H
0
2
2
2 2
-(CH ) O(CH ) -
C H CH
17
0
2
2
2 2
6
5
2
2
-(CH ) O(CH ) -
CH3
2
2
2 2
2
5
-(CH ) O(CH ) -
Thiophen-2-yl
C H
C H CH
29
0
2
2
2 2
6
5
5
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH3
6
5
5
5
f
CH(CH3)2
C H
C H
13
0
6
6
c
-(CH ) O(CH ) -
C H
H
2
2
2 2
6
Table 3 Bond Lengths [Å] for 5g
Atom
N(1)
Atom
C(5)
Distance
Atom
N(1')
Atom
C(5')
Distance
1.328(3)
1.381(2)
1.443(3)
1.318(2)
1.370(2)
1.387(2)
1.326(2)
1.497(3)
1.460(2)
1.469(2)
1.511(3)
1.431(2)
1.419(2)
1.519(3)
1.502(3)
1.329(2)
1.387(2)
1.441(3)
1.317(3)
1.365(2)
1.394(2)
1.327(2)
1.503(3)
1.456(3)
1.472(2)
1.509(3)
1.427(2)
1.416(2)
1.509(3)
1.496(3)
N(1)
N(2)
N(1')
N(2')
N(1)
C(11)
C(3)
N(1')
C(11')
C(3')
N(2)
N(2')
C(3)
N(4)
C(3')
N(4')
C(3)
N(31)
C(5)
C(3')
N(31')
C(5')
N(4)
N(4')
C(5)
C(51)
C(32)
C(36)
C(33)
O(34)
C(35)
C(36)
C(52)
C(5')
C(51')
C(32')
C(36')
C(33')
O(34')
C(35')
C(36')
C(52')
N(31)
N(31)
C(32)
C(33)
O(34)
C(35)
C(51)
N(31')
N(31')
C(32')
C(33')
O(34')
C(35')
C(51')
Melting points were determined using a capillary melting point ap-
paratus equipped with a digital thermometer and were uncorrected.
H and C NMR spectra were recorded on a Varian GEMINI-300
yl(2H-benzotriazol-2-yl)methanimine (1’), (utilized as a 2:1 mix-
ture of isomers) were prepared and characterized according to the
1
13
10a
previously published procedure.
MHz spectrometer (300 MHz and 75 MHz respectively) using
CDCl or DMSO-d (compound 7) as solvents with tetramethylsi-
Preparation of Benzotriazole-1-carboximidamides 2; General
Procedure
Di(benzotriazolyl)methanimines 1 and 1’ (500 mg, 2 mmol) was
suspended in dry THF (20 mL) under inert atmosphere. The appro-
priate amine (2 mmol, 1 equiv) was added dropwise, and the result-
ing mixture was allowed to react for 8–12 h until complete
3
6
lane as internal standard. THF was distilled under nitrogen immedi-
ately before use from sodium/benzophenone. All other reagents
were of reagent grade and were used without purification. Column
chromatography was conducted with silica gel 230–400 mesh.
Di(1H-benzotriazol-1-yl)methanimine (1) and 1H-benzotriazol-1-
Synthesis 2001, No. 6, 897–903 ISSN 0039-7881 © Thieme Stuttgart · New York

9
00
A. R. Katritzky et al.
PAPER
able 4 Bond Angles [°] for 5g
tom
Atom
N(1)
Atom
N(2)
Angle
Atom
C(5')
C(5')
N(2')
C(3')
N(2')
N(2')
N(4')
C(5')
N(4')
N(4')
N(1')
C(3')
C(3')
C(32')
N(31')
O(34')
C(35')
O(34')
N(31')
C(5')
Atom
N(1')
N(1')
N(1')
N(2')
C(3')
Atom
N(2')
Angle
(
(
5)
5)
110.19(17)
129.38(19)
120.21(17)
101.06(14)
115.85(17)
122.41(16)
121.71(18)
102.43(17)
110.46(18)
126.52(18)
122.90(18)
114.43(15)
115.18(15)
111.55(15)
109.65(16)
111.67(17)
109.71(16)
111.87(16)
109.73(16)
113.24(17)
110.78(17)
128.27(19)
120.70(17)
101.21(15)
115.18(16)
122.77(16)
122.02(17)
102.95(16)
109.85(18)
126.42(18)
123.64(19)
114.81(15)
115.79(16)
112.43(15)
109.00(17)
111.80(17)
109.74(16)
111.40(16)
109.19(16)
113.42(18)
N(1)
C(11)
C(11)
N(1)
C(11')
C(11')
N(1')
(
2)
N(1)
(
3)
N(2)
(
(
(
2)
2)
4)
C(3)
N(4)
N(4')
C(3)
N(31)
N(31)
C(3)
C(3')
N(31')
N(31')
C(3')
C(3)
C(3')
(
5)
N(4)
N(4')
C(5')
(
(
(
4)
4)
1)
C(5)
N(1)
N(1')
C(5)
C(51)
C(51)
C(32)
C(36)
C(36)
C(33)
C(32)
C(33)
C(36)
C(35)
C(5)
C(5')
C(51')
C(51')
C(32')
C(36')
C(36')
C(33')
C(32')
C(33')
C(36')
C(35')
C(52')
C(5)
C(5')
(
(
(
3)
N(31)
N(31)
N(31)
C(32)
C(33)
O(34)
C(35)
C(36)
C(51)
N(31')
N(31')
N(31')
C(32')
C(33')
O(34')
C(35')
C(36')
C(51')
3)
32)
(
(
31)
34)
(
35)
(
(
34)
31)
(
52)
1H NMR: = 1.24 (t, 6H, J = 7.1 Hz), 3.36 (q, 4H, J = 7.1 Hz), 6.64
(
(
br s, 1H), 7.45 (t, 1H, J = 7.5 Hz), 7.59 (t, 1H, J = 8.1 Hz), 7.72
br s, 1H), 8.11 (d, 1H, J = 8.3 Hz).
O
13C NMR: = 12.9, 43.0, 110.8, 120.0, 124.7, 128.8, 132.0, 145.3,
150.7.
NH2
N
H
N
N
8
This compound was used as crude product without isolation and pu-
rification for further transformation. See compound 3a.
O
NH2
1+1'
THF
reflux
N,N-Diallyl-1H-benzotriazole-1-carboximidamide (2b)
7
Colorless oil, yield 86%.
1H NMR: = 3.95–3.93 (d, 4H, J = 5.9 Hz), 5.23–5.17 (m, 4H),
Scheme 3
5
.97–5.84 (m, 2H), 7.44 (t, 1H, J = 7.7 Hz), 7.58 (t, 1H, J = 7.2
Hz), 7.75 (d, 1H, J = 8.2 Hz), 8.10 (d, 1H, J = 8.1 Hz).
conversion of 1, as monitored by TLC. The mixture was then con-
13C NMR:
= 50.8, 111.3, 118.3, 120.0, 124.7, 128.9, 132.1, 132.5,
45.4, 151.2.
Anal. Calcd for C13
64.33; H, 6.40; N, 29.22.
centrated in vacuo and dissolved in CH Cl (20 mL). The organic
2
2
1
layer was washed twice with aqueous Na CO (10%), dried over
2
3
MgSO , and the solvent removed under reduced pressure to afford
H N : C, 64.71; H, 6.27; N, 29.02. Found: C,
15 5
4
compounds 2a–d with analytical purity. The preparation and char-
acterization of compounds 2c,d were described previously in our
earlier work.1
0a
Preparation of Acyl Derivatives of 1H-Benzotriazol-1-
carboximidamides 3a–g; General Procedure
N,N-Diethyl-1H-benzotriazole-1-carboximidamide (2a)
Yellow oil, yield 95%.
Compound 2 (1 equiv) was dissolved in chloroform and acyl chlo-
ride (1 equiv) was added followed by addition of triethylamine
(1 equiv). The mixture was allowed to react for 2–4 h at ambient
temperature. The completion of the reaction was monitored by
Synthesis 2001, No. 6, 897–903 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of N,N-Disubstituted 3-Amino-1,2,4-triazoles
901
TLC. Then the chloroform solution was washed with water to re-
move triethylamine hydrochloride. The chloroform layer was sepa-
rated, dried and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel with ethyl ac-
etate–hexanes (1:1) as eluent for compounds 3b,e or by recrystalli-
zation for compounds 3a,c,d,g. The preparation and
characterization of compound 3f was described previously in our
earlier work.1
Anal. Calcd for C H N O S: C, 56.29; H, 4.43; N, 20.51. Found:
C, 56.30; H, 4.39; N, 20.49.
1
6
15
5
2
N-[1H-Benzotriazol-1-yl(morpholino)methylidene]propanamide
(3g)
White prisms, mp 56–57 °C, yield 91%.
1H NMR: = 1.01 (t, 3H, J = 7.2 Hz), 2.44 (q, 2H, J = 7.2 Hz),
0a
3
7
.46–3.51 (m, 4H), 3.82–3.85 (m, 4H), 7.42–7.48 (m, 1H), 7.60–
.62 (m, 2H), 8.10 (d, 1H, J = 7.6 Hz).
N-[1H-Benzotriazol-1-yl(diethylamino)methylidene]-2,2-dimeth-
ylpropanamide (3a)
White prisms, mp 106–108 °C, yield 62%.
13C NMR:
32.4, 143.9, 145.4, 185.0
= 8.9, 32.6, 47.4, 66.1, 110.5, 120.6, 125.2, 129.5,
1
1H NMR: = 1.15 (s, 9H), 1.27 (t, 6H, J = 7.1 Hz), 3.49 (q, 4H,
J = 6.8 Hz), 7.38–7.44 (m, 1H), 7.54 (s, 2H), 8.08 (d, 1H, J = 8.3
Anal. Calcd for C H N O : C, 58.52; H, 5.96. Found: C, 58.37; H,
14 17 5 2
5
.88.
Hz).
Preparation of 3-(N,N-Dialkyl)amino-1,5-disubstituted
Triazoles 5 and 6; General Procedure
13C NMR:
33.3, 144.9, 145.2, 189.3.
= 13.1, 27.4, 41.2, 43.6, 110.2, 120.4, 124.6, 128.8,
1
Compound 3 (1 equiv) was dissolved in chloroform and hydrazine
4 (1 equiv) was added. The completion of the reaction was moni-
tored by TLC. The mixture was concentrated under reduced pres-
sure. Separation and purification of compounds 5 and 6 were
performed by column chromatography using a mixture of ethyl ac-
etate/hexanes (1:1) as eluent for compounds 5a–d,j,k and 6b,g;
CHCl –MeOH (19:1) for compounds 5e,i,g,h, 6h; CH Cl –Et O
Anal. Calcd for C H N O: C, 63.76; H, 7.69; N, 23.24. Found: C,
16
23
5
6
4.06; H, 8.07; N, 23.35.
N-[1H-Benzotriazol-1-yl(diallylamino)methylidene]benzamide
3b)
(
White prisms, mp 87–88 °C, yield 74%.
3
2
2
2
1H NMR: = 4.13 (d, 4H, J = 6.0 Hz), 5.31–5.26 (m, 4H), 6.06–
(9:1) for compounds 5f, 6f.
5
3
.93 (m, 2H), 7.40–7.26 (m, 5H), 7.51–7.46 (m, 1H), 8.08–7.99 (m,
H).
5
-(tert-Butyl)-N,N-diethyl-1-methyl-1H-1,2,4-triazol-3-amine (5a)
Colorless oil, yield 75%.
1H NMR: = 1.13 (t, 6H, J = 7.1 Hz), 1.39 (s, 9H), 3.39 (q, 4H,
J = 7.0 Hz), 3.78 (s, 3H).
13C NMR:
31.5, 132.2, 132.6, 135.3, 145.1, 147.3, 174.5.
= 51.5, 110.4, 119.6, 120.4, 124.8, 128.0, 129.1, 129.5,
1
Anal. Calcd for C H N O: C, 69.55; H, 5.54; N, 20.28. Found: C,
6
20
19
5
13C NMR:
= 12.8, 28.9, 32.2, 37.1, 41.7, 160.6, 162.7.
9.56; H, 5.85; N, 20.25.
Anal. Calcd for C H N : C, 62.82; H, 10.54; N, 26.64. Found: C,
1
1
22
4
N-[1H-Benzotriazol-1-yl(morpholino)methylidene]-1-naphth-
amide (3c)
62.75; H, 10.83; N, 26.89.
White prisms, mp 153–154 °C, yield 94%.
1-Benzyl-5-(tert-butyl)-N,N-diethyl-1H-1,2,4-triazol-3-amine (5b)
1H NMR: = 3.67–3.70 (m, 4H), 3.88–3.92 (m, 4H), 7.36–7.55 (m,
Colorless oil, yield 36%.
6
H), 7.80 (dd, 1H, J = 7.6 Hz, J = 1.7 Hz), 7.93 (d, 1H, J = 8.2
Hz), 8.05–8.08 (m, 1H), 8.25 (dd, 1H, J = 7.3 Hz, J = 1.3 Hz), 8.47
dd, 1H, J = 8.2 Hz, J = 1.3 Hz).
1H NMR: = 1.15 (t, 6H, J = 7.1 Hz), 1.32 (s, 9H), 3.43 (q, 4H,
J = 7.1 Hz), 5.33 (s, 2H), 7.07 (d, 2H, J = 7.1 Hz), 7.22–7.29 (m,
3H).
(
13C NMR:
= 47.9, 66.3, 110.8, 120.4, 124.3, 125.1, 125.9, 126.0,
27.3, 128.2, 129.5, 130.4, 131.0, 132.4, 132.5, 132.8, 133.7, 145.4,
46.0, 177.0.
13C NMR: = 12.7, 29.5, 32.6, 41.8, 52.6, 126.1, 127.1, 128.4,
137.5, 161.4, 163.0.
1
1
Anal. Calcd for C H N : N, 19.56. Found: N, 19.39.
1
1
22
4
Anal. Calcd for C H N O : C, 68.56; H, 4.97; N, 18.17. Found: C,
2
2
19
5
2
6
8.78; H, 5.00; N, 18.38.
N,N-Diallyl-N-(5-phenyl-1H-1,2,4-triazol-3-yl)amine (5c)
White microcrystals, mp 116–117 °C, yield 72%.
N-[1H-Benzotriazol-1-yl(morpholino)methylidene]benzamide (3d)
White prisms, mp 183–184 °C, yield 93%.
1H NMR: = 3.65 3.68 (m, 4H), 3.89 3.92 (m, 4H), 7.37 7.53
1H NMR: = 4.04 (d, 4H, J = 5.5 Hz), 5.16 5.25 (m, 4H), 5.78
5
.87 (m, 2H), 7.26 7.36 (m, 3H), 7.80 (br s, 1H), 7.94 7.98 (m,
2H).
(
m, 6H), 8.01 8.10 (m, 3H).
13C NMR:
= 48.0, 66.3, 110.9, 120.5, 125.1, 128.1, 129.4, 129.6,
32.4, 132.5, 135.2, 145.5, 147.0, 174.9.
Anal. Calcd for C H N O : C, 64.47; H, 5.11; N, 20.88. Found: C,
13C NMR:
159.5.
= 51.1, 117.7, 126.4, 128.5, 129.4, 129.8, 133.1, 158.2,
1
Anal. Calcd for C H N : C, 69.97; H, 6.71; N, 23.31. Found: C,
70.27; H, 7.00; N, 23.55.
1
4
16
4
1
8
17
5
2
6
4.63; H, 5.51; N, 21.05.
N,N-Diallyl-N-(3-methyl-5-phenyl-1H-1,2,4-triazol-3-yl)amine
N-[1H-Benzotriazol-1-yl(morpholino)methylidene]-2-thio-
phenecarboxamide (3e)
(5d)
Colorless oil, yield 84%.
White prisms, mp 148–150 °C, yield 64%.
1H NMR: = 3.68–3.71 (m, 4H), 3.91–3.94 (m, 4H), 7.08 (t, 1H,
J = 4.3 Hz), 7.40–7.55 (m, 4H), 7.71 (d, 1H, J = 3.4 Hz), 8.11 (d,
1H NMR: = 3.78 (s, 3H), 4.06 (d, 4H, J = 5.8 Hz), 5.14 5.24 (m,
4H), 5.83 5.96 (m, 2H), 7.43 7.48 (m, 3H), 7.60 7.63 (m, 2H).
13C NMR:
= 36.2, 49.7, 116.6, 128.4, 128.5, 128.6, 129.6, 134.3,
1
H, J = 8.1 Hz).
13C NMR:
= 48.2, 66.3, 111.0, 120.5, 125.2, 128.0, 129.6, 132.4,
32.5, 141.2, 145.5, 147.4, 169.1.
1
53.8, 164.2.
Anal. Calcd for C H N : C, 70.84; H, 7.13; N, 22.03. Found: C,
1
5
18
4
1
7
0.53; H, 7.17; N, 22.45.
Synthesis 2001, No. 6, 897–903 ISSN 0039-7881 © Thieme Stuttgart · New York

9
02
A. R. Katritzky et al.
PAPER
4
-[1-Methyl-5-(1-naphthyl)-1H-1,2,4-triazol-3-yl]morpholine (5e)
Anal. Calcd for C H N : C, 74.97; H, 7.55; N, 17.48. Found: C,
2
0
24
4
White prisms, mp 115–117 °C, yield 90%.
74.96; H, 7.97, N, 17.52.
1H NMR: = 3.49–3.51 (m, 4H), 3.60 (s, 3H), 3.84–3.88 (m, 4H),
4
-(5-Phenyl-1H-1,2,4-triazol-3-yl)morpholine (5k)
7
8
.52–7.58 (m, 4H), 7.76–7.78 (m, 1H), 7.90–7.93 (m, 1H), 7.96
.00 (m, 1H).
White microcrystals, mp 128 129 °C, yield 84%.
1H NMR: = 3.32 3.35 (m, 4H), 3.63 3.66 (m, 4H), 7.34 7.36
13C NMR:
= 35.7, 46.9, 66.5, 124.9, 125.0, 125.6, 126.5, 127.3,
(
m, 3H), 7.85 7.88 (m, 2H), 9.22 (br s, 1H).
13C NMR:
= 46.6, 66.0, 126.2, 128.7, 129.0, 129.8, 157.7, 162.4.
Anal. Calcd for C H N O: C, 62.59; H, 6.13; N, 24.33. Found: C,
1
28.3, 128.4, 130.5, 131.5, 133.5, 153.2, 165.4.
Anal. Calcd for C H N O: N, 19.03. Found: N, 19.04.
17
18
4
1
2
14
4
4
-[1-Benzyl-5-(1-naphthyl)-1H-1,2,4-triazol-3-yl]morpholine (5f)
62.26; H, 6.49, N, 23.94.
Off-white microcrystals, mp 125–127 °C, yield 45%.
1H NMR: = 3.50–3.53 (m, 4H), 3.83–3.86 (m, 4H), 5.02 (s, 2H),
1-[1-Benzyl-5-(tert-butyl)-1H-1,2,4-triazol-3-yl]-1H-benzotriazole
(
6b)
7
1
7
.00–7.03 (m, 2H), 7.19–7.24 (m, 3H), 7.44–7.55 (m, 4H), 7.75 (dd,
H, J = 6.5 Hz, J = 1.5 Hz), 7.89 (dd, 1H, J = 5.3 Hz, J = 1.8 Hz),
.96 (dd, 1H, J = 5.0 Hz, J = 2.2 Hz).
White prisms, mp 134–135 °C, yield 30%.
1H NMR: = 1.51 (s, 9H), 5.63 (s, 2H), 7.22 (d, 2H, J = 6.6 Hz),
7.31–7.36 (m, 3H), 7.44 (t, 1H, J = 7.1 Hz), 7.59 (t, 1H, J = 7.1
Hz), 8.13 (d, 1H, J = 8.3 Hz), 8.28 (d, 1H, J = 8.3 Hz).
13C NMR:
= 46.9, 52.2, 66.5, 124.8, 125.1, 125.6, 126.5, 127.2,
1
1
27.3, 127.7, 128.2, 128.3, 128.4, 130.6, 131.6, 133.5, 135.9, 153.3,
65.5.
13C NMR: = 29.4, 33.3, 54.1, 112.9, 119.9, 124.7, 126.5, 128.0,
1
28.7, 128.8, 131.6, 135.5, 145.9, 153.9, 163.8.
Anal. Calcd for C H N O: N, 15.12. Found: N, 14.92.
23
22
4
Anal. Calcd for C H N : C, 68.29; H, 6.06; N, 25.28. Found: C,
1
9
20
6
4
-(5-Ethyl-1-methyl-1H-1,2,4-triazol-3-yl)morpholine (5g)
68.29; H, 6.46, N, 24.98.
White prisms, mp 87–89 °C, yield 82%.
1H NMR: = 1.29 (t, 3H, J = 7.6 Hz), 2.66 (q, 2H, J = 7.5 Hz),
1-[1-Benzyl-5-(1-naphthyl)-1H-1,2,4-triazol-3-yl]-1H-benzo-
triazole (6f)
Yellow oil, yield 17%.
1H NMR: = 5.31 (s, 2H), 7.10–7.13 (m, 2H), 7.24–7.26 (m, 3H),
7.47–7.64 (m, 6H), 7.77 (d, 1H, J = 7.6 Hz), 7.98 (d, 1H, J = 8.1
Hz), 8.05–8.10 (m, 1H), 8.17 (dt, 1H, J = 8.3 Hz, J = 1.0 Hz), 8.36
3
.34–3.37 (m, 4H), 3.67 (s, 3H), 3.78–3.81 (m, 4H).
13C NMR:
= 11.9, 19.3, 34.4, 46.9, 66.4, 156.1, 164.6
Anal. Calcd for C H N O: C, 55.08; H, 8.82; N, 28.55. Found: C,
9
16
4
5
5.24; H, 8.82; N, 28.27.
(
dt, 1H, J = 8.3 Hz, J = 1.0 Hz).
Crystal data for 5g: C H N O, MW 196.26, monoclinic, P2 ,
9
16
4
1
a = 6.862(2) Å,
b = 15.206(5)
Å, c = 10.245(4) Å,
13C NMR:
= 53.4, 98.1, 113.0, 120.0, 124.3, 124.8, 124.9, 124.9,
o
Å3, Z = 4, T = –110°C,
=
109.482(4) , V = 1007.7(6)
1
26.8, 127.7, 127.8, 128.4, 128.6, 128.7, 128.8, 129.0, 131.4, 131.5,
–
1
.
–3
o
(
MoK ) = 0.089 mm , D
= 1.294 g cm , 2
53 (SMART
calcd
max
131.7, 133.5, 134.7, 146.0, 154.9.
2
CCD area detector), wR(F ) = 0.0903 (all 3839 data), R = 0.0375
3193 data with I > 2 I).
Anal. HRMS (FAB) Calcd for C H N (M + 1): 403.1671. Found:
2
5
19
6
(
4
03.1666.
4
-[1-Benzyl-5-(2-thienyl)-1H-1,2,4-triazol-3-yl]morpholine (5h)
1
-[1-Benzyl-5-(2-thienyl)-1H-1,2,4-triazol-3-yl]-1H-benzotriazole
Greenish microcrystals, mp 114–116 °C, yield 42%.
1H NMR: = 3.45–3.48 (m, 4H), 3.80–3.83 (m, 4H), 5.40 (s, 2H),
7
Hz).
13C NMR:
1
(
6h)
Off-white solid, mp 148–150 °C, yield 29%.
1H NMR: = 5.63 (s, 2H), 7.07 (t, 1H, J = 3.7 Hz), 7.22–7.58 (m,
.04 (t, 1H, J = 3.8 Hz), 7.17–7.37 (m, 6H), 7.42 (d, 1H, J = 4.9
9
H), 8.08 (d, 1H, J = 8.4 Hz), 8.28 (d, 1H, J = 8.5 Hz).
13C NMR:
= 53.5, 112.9, 120.0, 124.9, 126.7, 127.7, 128.1, 128.4,
29.0, 129.1, 129.6, 129.8, 131.6, 134.7, 146.0, 150.4, 155.3.
Anal. Calcd for C H N : C, 63.67; H, 3.94. Found: C, 63.58; H,
= 46.8, 52.4, 66.5, 126.4, 127.7, 127.8, 128.0, 128.4,
28.8, 129.1, 135.9, 148.6, 165.1.
1
Anal. Calcd for C H N OS: C, 62.55; H, 5.56. Found: C, 62.48; H,
5
17
18
4
1
9
14
6
.59.
4
.19.
N,N-Diisopropyl-1-methyl-5-phenyl-1H-1,2,4-triazol-3-amine (5i)
Off-white prisms, mp 41–43 °C, yield 95%.
1H NMR: = 1.33 (d, 12H, J = 6.7 Hz), 3.78 (s, 3H), 4.02–4.15 (m,
1
-(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)-1H-benzotriazole (6j)
White prisms, mp 170–180 °C, yield 13%.
1H NMR: = 7.38–7.51 (m, 9H), 7.62–7.67 (m, 3H), 8.18 (dd, 1H,
J = 0.8 Hz, J = 7.6 Hz), 8.42 (dd, 1H, J = 0.8 Hz, J = 7.6 Hz).
2
H), 7.39–7.48 (m, 3H), 7.60–7.65 (m, 2H).
13C NMR:
= 20.7, 36.2, 46.3, 128.5, 128.6, 128.9, 129.3, 152.7,
62.9.
Anal. Calcd for C H N : C, 69.73; H, 8.58; N, 21.68. Found: C,
13C NMR:
29.1, 129.5, 129.6, 130.7, 131.6, 137.6, 146.0, 154.7, 156.0.
= 112.9, 120.1, 124.9, 125.6, 126.7, 128.7, 129.0,
1
1
15
22
4
Anal. Calcd for C H N : C, 70.99; H, 4.17; N, 24.84. Found: C,
7
2
0
14
6
6
9.59; H, 8.67, N, 22.02.
0.98; H, 4.45, N, 24.78.
N,N-Diisopropyl-1,5-diphenyl-1H-1,2,4-triazol-3-amine (5j)
White prisms, mp 188–189 °C, yield 25%.
1H NMR: = 1.37 (d, 12H, J = 6.8 Hz), 4.11–4.19 (m, 2H), 7.26–
Preparation of 5-Phenyl-1,3,4-oxadiazol-2-ylamine 7
Compound 1 (0.5 g, 1.9 mmol) and benzoic hydrazide (0.29 g,
1
.9 mmol) were dissolved in THF (25 mL) and heated under reflux
7
.33 (m, 8H), 7.44–7.48 (m, 2H).
for 3 h. Compound 7 precipitated after cooling of the reaction mix-
ture. The precipitate was filtered off and washed with cold THF to
give compound 7 as white needles 0.575 g (94%); mp 240–241 °C.
13C NMR:
= 20.7, 46.4, 124.9, 127.4, 128.3, 128.8, 128.9, 129.1,
1
29.2, 138.7, 151.5, 163.3.
1H NMR:
7.30 (s, 2H), 7.53 7.58 (m, 3H), 7.81 7.84 (m, 2H).
Synthesis 2001, No. 6, 897–903 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of N,N-Disubstituted 3-Amino-1,2,4-triazoles
903
13C NMR:
= 124.4, 125.0, 129.2, 130.4, 157.4, 163.9.
(7) (a) Temple, C. Jr. In Triazoles 1,2,4; Mongomery, J. A., Ed.;
John Wiley and Sons: New York, 1981, 130. (b) Polya, J.
B. In Comprehensive Heterocyclic Chemistry, Vol. 5; Potts,
K. T., Ed.; Pergamon Press: Oxford, 1984, 733.
Anal. Calcd for C H N O: C, 59.62; H, 4.38; N, 26.07. Found: C,
8
7
3
5
9.61, H, 4.26, N, 26.26.
(
c) Mullican, M. D.; Wilson, M. W.; Connor, D. T.; Kostlan,
C. R.; Schrier, D. J.; Dyer, R. D. J. Med. Chem. 1993, 36,
090. (d) Lipinski, C. A.; LaMattina, J. L.; Hohnke, L. A. J.
References
1
(
1) (a) Khadir, A.; Verreault, J.; Averill, D. A. Archives of
Biochemistry and Biophysics 1999, 370, 163. (b) Pedraza-
Chaverri, J.; de los Granados-Silvestre, M. A.; Medina-
Campos, O. N.; Hernandez-Pando, R. Free Radical Biology
Med. Chem. 1985, 28, 1628. (e)Gyorgydeak, Z.;Holzer, W.
Heterocycles 1998, 48, 1395.
8) (a) Reimlinger, H.; Billiau, F.; Lingier, W. R. F. Synthesis
(
(
1970, 260. (b) Reimlinger, H.; Lingier, W. R. F.;
&
Medicine 1999, 27, 245. (c) Streb, P.; Feierabend, J.
Vandewalle, J. J. M.; Goes, E. Synthesis 1970, 433.
Botanica Acta 1996, 109, 125. (d) Matsuda, Y.; Okuda, T.;
Sagisaka, S. Biosci. Biotech. Biochem. 1994, 58, 906.
2) Ventura, L.; PerezGonzales, J. A.; Ramon, D. Fems
Microbiology Lett. 1997, 149, 207.
9) (a) von Kristinsson, H.; Winkler, T. Helv. Chim. Acta 1983,
66, 1129. (b) Heitke, B. T.; McCarty, C. G. J. Org. Chem.
(
(
1974, 39, 1522. (c) Hoggarth, E. J. Chem. Soc. 1950, 1579.
(
d) Akahoshi, F.; Okada, T.; Takeda, S.; Naito, Y.; Fukaya,
3) Naito, Y.; Akahoshi, F.; Takeda, S.; Okada, T.; Kajii, M.;
Nishimura, H.; Sigiura, M.; Fukaya, C.; Kagitani, Y. J. Med.
Chem. 1996, 39, 3019.
C.; Kuwahara, S.; Kajii, M.; Nishimura, H.; Sugiura, M. WO
95/03286, 1995. (e) Okide, G. B. Indian J. Chem., Sect. B
1993, 32, 422. (f) Chem. Abstr. 1966, 64, 8196.
(
(
(
4) Stemp, G.; Burrell, G. Eur. Patent Appl. EP 399834, 1990.
5) Clitherow, J. W. Eur. Patent Appl. EP 367484, 1989.
6) (a) Wermann, K.; Hartmann, M.; Bauer, H.-J. Z. Chem.
(
10) (a) Katritzky, A. R.; Rogovoy, B. V.; Chassaing, C.;
Vvedensky, V. J. Org. Chem. 2000, 65, 8080.
(
b) Katritzky, A. R.; Pleynet, D. P. M.; Yang, B. J. Org.
1984, 24, 120. (b) Hartmann, M.; Bauer, H.-J.; Wermann,
Chem. 1997, 62, 4155.
K. Biocide Polymers 1985, 195.
Synthesis 2001, No. 6, 897–903 ISSN 0039-7881 © Thieme Stuttgart · New York