1,3-Dipolar Cycloaddition of Carbodiimides and Nitrilimines: Synthesis and Mechanistic Study of 5-Amino-1,2,4-triazoles

Article abstract of DOI:10.1002/ejoc.201600240

An effective 1,3-dipolar cycloaddition was developed for the synthesis of 5-amino-1,2,4-triazoles by reacting hydrazonoyl hydrochlorides (nitrilimines) with carbodiimides in the presence of triethylamine as a base. Both symmetric and asymmetric carbodiimi

Full text of DOI:10.1002/ejoc.201600240

DOI: 10.1002/ejoc.201600240
Full Paper
Dipolar Cycloadditions
1,3-Dipolar Cycloaddition of Carbodiimides and Nitrilimines:
Synthesis and Mechanistic Study of 5-Amino-1,2,4-triazoles
Wan-Ping Yen,[a,b][‡] Fung-Chun Kung,[c][‡] and Fung Fuh Wong*[a,b,c]
Abstract: An effective 1,3-dipolar cycloaddition was developed reaction; diphenyl carbodiimide is the one exception. Mechanis-
for the synthesis of 5-amino-1,2,4-triazoles by reacting hydraz- tic studies indicate that alkyl and cycloalkyl moieties of the qua-
onoyl hydrochlorides (nitrilimines) with carbodiimides in the ternary N+–R on the 1,2,4-triazolic ring serve as potential leav-
presence of triethylamine as a base. Both symmetric and asym- ing groups and can efficiently depart from the intermediate 4,5-
metric carbodiimides are compatible with this newly developed dihydro-4-alkyl-5-imino-1,2,4-triazole.
Introduction
Polysubstituted 1,2,4-triazoles are an important class of hetero-
cyclic compounds that display versatile biological activities.[1] In
particular, the 5-amino-1,2,4-triazoles have drawn considerable
attention due to their potential pharmaceutical applications in
medicinal chemistry.[2–5] The typical synthetic methods for the
preparation of 5-amino-1,2,4-triazoles involve thermal conden-
sations between hydrazonoyl derivatives and cyanamide[6–9] or
Figure 1. Two general synthetic pathways to 5-amino-1,2,4-triazoles.
between N-cyanoimidates and mono-substituted hydrazines
(see Figure 1).[10–13] However, both methods suffer from low
yields, harsh reaction conditions, and requisite long reaction
compounds,[23] thiadiazoles,[24] 1,2,3-triazoles[25] and 1,2,4-tri-
times. Although other approaches using 1,3,4-thiadiazol-2-
azoles.[26] However, 1,3-dipolar cycloaddition of carbodiimides
amines[14] or aminoguanidine[15] as the starting materials have
with nitrilimines is rarely described in early reports.[27] In this
also been reported, these compounds are not commercially
work, we report an efficient and convenient synthetic route to
available and require multi-step preparations coupled with tedi-
5-amino-1,2,4-triazoles and 1,2,4-triazoles via a 1,3-dipolar
ous purification procedures.[14,15] As a result, the development
cycloaddition of hydrazonoyl hydrochlorides with both sym-
of a synthetic method for direct preparation of 5-amino-1,2,4-
metric and asymmetric carbodiimides in the presence of tri-
triazoles is particularly desirable.
ethylamine. Based on the mechanistic studies, the alkyl and
Carbodiimides are valuable functional groups for synthetic
cycloalkyl units of the quaternary N+–R moieties on the 1,2,4-
chemistry, since they can be transferred to ureas,[16] imido
triazolic scaffold appear to function as leaving groups; such
carbonates,[17] imido amides,[18] guanidines,[19] oxazolidinone
groups can depart from transiently formed 4,5-dihydro-4-alkyl-
derivatives[20] as well as aromatic and non-aromatic hetero-
5-imino-1,2,4-triazole intermediate to generate 5-amino-1,2,4-
cycles.[21] Conversely, hydrazonoyl hydrochlorides are attractive
molecules because they serve as versatile precursors to the 1,3-
triazole products. The isolation and characterization of triethyl
tert-butylammonium chloride as the by-product provide strong
dipolar cycloaddition reaction associated with generating five-
evidence supporting the proposed mechanism. Further con-
membered heterocycles including pyrazoles,[22] pyrazole-fused
trolled experimental studies demonstrated that the activity and
stability order of carbocation groups are: tert-butyl (3° carbo-
cation) > cyclopentyl (2° carbocation) > isopropyl (2° carbo-
cation) > cyclohexyl (2° carbocation) > ethyl (1° carbo-
cation) >> phenyl (not detectable).
[a] School of Pharmacy, China Medical University,
No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, R.O.C.
E-mail: ffwong@mail.cmu.edu.tw
wongfungfuh@yahoo.com.tw
http://webap.cmu.edu.tw/TchEportfolio/index_1/ffwong
[b] The Ph.D. Program for Biotech Pharmaceutical Industry,
China Medical University,
No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan, R.O.C.
[c] Graduate Institute of Pharmaceutical Chemistry, China Medical University,
No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, R.O.C.
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600240.
Results and Discussion
A common feature of carbodiimides,[28] imidates,[29] and ox-
imes[30] is that they all possess an imine functional group which
can be used to construct heterocyclic aromatic compounds.[31]
For instance, we have previously reported that the 1,3-dipolar
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Scheme 1. Our previously reported synthesis of 1,3,5-trisubstituted 1,2,4-triazoles via 1,3-dipolar cycloaddition reaction of nitrilimines with aldehydes, nitriles,
imidate hydrochlorides, or oxime hydrochlorides.
cycloaddition of nitrilimines with aldehydes, nitriles, imidate
All 5-amino-1,2,4-triazoles 3a–f, 4a–f, and 5a–f were fully
hydrochlorides, or oxime hydrochlorides can produce a series characterized by spectroscopic methods including a single-crys-
of 1,3,5-trisubstituted 1,2,4-triazoles (see Scheme 1).[26]
By employing the same reaction conditions shown in
Scheme 1 and Scheme 2, we investigated the possibility of con-
verting chemically similar carbodiimide compounds to their
corresponding 1,2,4-triazoles (see Scheme 2). To start, we first
extended this newly developed method to symmetric carbo-
diimides including diisopropylcarbodiimide 1a, di-tert-butyl-
carbodiimide 1b, dicyclohexylcarbodiimide 1c and diphenyl-
carbodiimide 1d (see Scheme 2).
tal X-ray diffraction study (ORTEP) for compound 4c. In 1H NMR
spectra of 4c, resonances at δ = 1.42 ppm for tert-C(CH3)3 and
3.94 ppm for –OCH3 were observed. In 13C NMR spectra of com-
pound 4c, representative resonances at δ = 29.1 ppm for tert-
C(13CH3)3, 52.6 ppm for tert-13C(CH3)3, 152.6 and 154.0 ppm for
1,2,4-triazolic ring and δ = 160.7 ppm for the carbonyl carbon
13CH=O were detected. The IR absorptions for compound 4c
showed peaks at 1730 cm–1 for stretching of the methyl ester
group. The ORTEP drawing of compound 4c is shown in Fig-
ure 2.
The reaction was carried out by reacting carbodiimides
1a–d with various hydrazonoyl chlorides 2a–f bearing different
To reconfirm the lack of reactivity of diphenylcarbodiimide
N1 aryl substituents such as when X=H, p-F, p-Cl, p-Me, p-CF3, 1d, we designed and synthesized a series of asymmetric carbo-
or p-OMe (Table 1). The 1,3-dipolar cycloaddition went diimides,[32] including ethylphenylcarbodiimide 1e, isopropyl-
smoothly to give corresponding 5-amino-1,2,4-triazoles 3a–f, phenylcarbodiimide 1f, tert-butylphenylcarbodiimide 1g, cyclo-
4a–f, and 5a–f in 60–96 % yields, except for when diphenyl- pentylphenylcarbodiimide 1h, and cyclohexylphenylcarbodi-
carbodiimide 1d was used as the dipolarophile where no de- imide 1i, in order identify the substitution moiety at the N-
sired product was observed (see Scheme 2 and Table 1). In the position of carbodiimide (–N=C=N–). By adopting the same re-
reaction of 1d with 2e, diphenylurea and p-chloroaniline were action conditions, hydrazonoyl hydrochloride 2e was used as
isolated as the hydrolysis and decomposition products of 1d the model 1,3-dipolar reactant to react with asymmetric carbo-
and 2e, respectively.
diimides 1e–i (Table 2). The 1,3-dipolar cycloaddition smoothly
Scheme 2. The new developed 1,3-dipolar cycloaddition for synthesis of 5-amino-1,2,4-triazoles using hydrazonoyl hydrochlorides with symmetric or asymmet-
ric carbodiimides in the presence of triethylamine.
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Table 1. Synthesis of 5-amino-1,2,4-triazole derivatives 3a–f, 4a–f, and 5a–f
using carbodiimides 1a–d with various hydrazonoyl hydrochlorides 2a–f.
groups with substitutions of X = H, p-F, p-Me, and p-CF3
(Table 2). Accordingly, corresponding 5-amino-1,2,4-triazoles
6a–d were smoothly obtained in good to excellent yields (32–
76 %, Table 2, Entries 6–9 ).
Table 2. Synthesis of 5-amino-1,2,4-triazole derivatives using asymmetric
carbodiimides 1e–i with hydrazonoyl hydrochlorides 2a–e.
Entry
R
X
Yield [%]
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1d
iPr
iPr
iPr
iPr
iPr
iPr
tBu
tBu
tBu
tBu
tBu
tBu
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
Ph
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2f
H
85
88
91
92
96
91
89
69
93
78
72
60
86
91
73
96
82
91
p-Me
p-CF3
p-F
p-Cl
p-OMe
H
p-Me
p-CF3
p-F
p-Cl
p-OMe
H
p-Me
p-CF3
p-F
p-Cl
p-OMe
H
Entry
R
X
Yield [%]
6e
9
1
2
3
4
5
6
7
8
9
1e
1f
1g
1h
1i
1g
1g
1g
1g
Et
iPr
tBu
cyclopentyl
cyclohexyl
tBu
tBu
tBu
2e
2e
2e
2e
2e
2a
2b
2c
2d
p-Cl
49
61
94
72
50
41
76
32
63
10
11
12
13
14
15
16
17
18
19
p-Cl
p-Cl
p-Cl
p-Cl
H
p-Me
p-CF3
p-F
6e
6e
6e
6e
6a
6b
6c
6d
tBu
2a
0
To realize the different reactivity between dialkylcarbodiim-
ides and diphenylcarbodiimide, we selected asymmetric carbo-
gave corresponding 5-amino-1,2,4-triazole 6e in good yields diimides 1e–i as the model cases to explore and account for
(49–94 %, Table 2, Entries 1–5). Based on the result of control our proposed mechanism (see Scheme 3). At first, hydrazonoyl
experiments, we found the order of activity for alkyl or cyclo- hydrochloride 2e was converted to nitrilimine species 7 in the
alkyl groups of asymmetric carbodiimides to be tert-butyl > presence of an excess amount of triethylamine. Consequently,
cyclopentyl > isopropyl > cyclohexyl > ethyl >> phenyl. To real- asymmetric carbodiimide dipolarophiles 1e–i were treated with
ize the generality of this 1,3-dipolar cycloaddition reaction, we nitrilimine 7 to give cycloadduct dihydrotriazole intermediate 8,
subjected the best dipolarophile tert-butyl-phenylcarbodiimide the immediate 1,3-dipolar cycloaddition adduct. The less stable
1g to hydrazonoyl chlorides 2a–d bearing assorted N1 aryl conformer 8, a putatively kinetic product, was then converted
Figure 2. The ORTEP diagram of methyl 1-[4-trifloromethylphenyl]-5-(tert-butylamino)-1H-1,2,4-triazole-3-carboxylate (4c).
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Scheme 3. Predicted mechanism of asymmetric alkyl phenylcarbodiimide or symmetric diphenylcarbodiimide 1d reacting with nitrilimines in a 1,3-dipolar
cycloaddition.
to conformer 9, which is more stable on the basis of resonance
effects. We then came to realize that the alkyl or cycloalkyl unit
of the quaternary N+–R moiety of 4,5-dihydro-5-imino-1H-1,2,4-
triazole intermediate 9 can serve as a leaving group thus form-
ing alkyl or cycloalkyl carbocations by an E1 reaction. Such
carbocations, once formed, can be stabilized and trapped by
triethylamine thus affording quaternary triethyl alkyl or cyclo-
alkyl ammonium chloride salts. Notably, following routine work-
up, triethyl tert-butylammonium chloride, a clearly relevant by-
1
product, was isolated and identified by H-NMR spectroscopy
providing support for postulated mechanism (Figure 3). Alterna-
tively, our experimental results are also consistent with reported
carbocation stabilities dictating that the order of activity for
asymmetric carbodiimides follows the trend that tert-butyl
(3° carbocation) > cyclopentyl (2° carbocation) > isopropyl
(2° carbocation) > cyclohexyl (2° carbocation) > ethyl (1° carbo-
Figure 3. 1H NMR spectrum of triethyl tert-butylammonium chloride.
cation) >> phenyl cation. Finally, corresponding 5-amino-1,2,4-
triazole 6a–e products were obtained in 32–94 % yields
(Table 2). However, cycloadduct dihydrotriazole intermediates
10 or 11 should be not efficiently formed in view of the noted
instability of phenyl carbocations. As a result, 1,3-dipolar cyclo-
additions involving the Ph–N=C moiety of asymmetric alkyl or
cycloalkylphenylcarbodiimides 1e–i or symmetric diphenyl-
carbodiimide 1d with nitrilimine species 7 are unproductive.
ferent solvents, including toluene, THF, CH2Cl2, MeOH, dioxane,
and DMF were evaluated as reaction media. In aprotic solvents
(toluene, THF, and CH2Cl2), 5-amino-1,2,4-triazole 4e was ob-
tained in good yields (72 %, 73 %, and 74 %, respectively, see
We speculate that solvent does not play a vital role in this Table 3, Entries 1–3). In protic solvents such as MeOH, 4e was
reaction due to the fact that 1,3-dipolar cycloadditions involve obtained in 68 % yield. Interestingly, the 1,3-dipolar cycloaddi-
a concerted process and the transition state is non-polar. To tion failed to occur in polar solvents such as dioxane and DMF.
confirm this hypothesis, we carried out cycloaddition of di-tert- Hence, our experimental results are in agreement with previ-
butylcarbodiimide 1b with hydrazonoyl hydrochloride 2e. Dif- ously reported findings.[33]
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High-resolution mass spectra were obtained by means of a JEOL
JMS-HX110 mass spectrometer.
Table 3. Study of solvent effect by using di-tert-butylcarbodiimide 1b with
hydrazonoyl hydrochlorides 2e.
Standard Procedure of Synthesis of 5-Amino-1,2,4-triazoles
3a–f, 4a–f, 5a–f, and 6a–e: A solution of symmetric carbodiimides
(1a–d, 1.5 mmol, 1.5 equiv.) or asymmetric carbodiimides (1e–i,
1.5 mmol, 1.5 equiv.) was stirred at room temperature in toluene
solution (10 mL) for 0.5 h. Then triethylamine (3.0 mmol, 3.0 equiv.)
and various hydrazonoyl hydrochlorides (2a–f, 1.0 mmol, 1.0 equiv.)
were added into the reaction mixture and heated to reflux within
5 h. When the reaction was complete, the reaction mixture was
neutralized with aqueous 3
N HCl, added to water (10 mL) and
Entry
Reaction solvent
Reaction temp. [°C]
Yield [%] of 4e
extracted with CH2Cl2 (3 × 30 mL). The organic extracts were dried
with MgSO4, filtered, and concentrated under reduced pressure. The
residue solution was purified by column chromatography on silica
gel to give corresponding 5-amino-1,2,4-triazoles 3a–f, 4a–f, 5a–f,
and 6a–e in 53–96 % yields.
1
2
3
4
5
6
toluene
THF
CH2Cl2
MeOH
dioxane
DMF
110–120
60–75
45–55
65–75
100–110
150–160
72
73
74
68
[a]
–
–
Methyl 1-Phenyl-5-(isopropylamino)-1H-1,2,4-triazole-3-carb-
oxylate (3a): Yellow solid; m.p. 150–154 °C. 1H NMR (200 MHz,
CDCl3): δ = 0.99 (d, J = 6.9 Hz, 3 H, CH3), 1.34 (d, J = 6.9 Hz, 3 H,
CH3), 3.57 (sep, J = 6.9 Hz, 1 H), 3.96 (s, 3 H, OCH3), 6.80–6.89 (m, 2
H, ArH), 7.10–7.18 (m, 3 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ =
20.61, 22.50, 29.65, 45.94, 52.91, 115.02 (2 × CH), 122.02, 129.02 (2 ×
[a]
[a] Non-detectable.
Conclusions
CH), 136.51, 139.28, 159.48 ppm. IR (KBr): ν = 2924 (m), 1732 (s, C=
˜
O), 1600 (m), 1469 (m), 1319 (m), 1257 (s, C–O), 1124 (m), 750 (m),
690 (m) cm–1. EIMS: m/z (%) = 260 (22) [M]+, 229 (25), 218 (54), 212
(36), 197 (37), 118 (39), 105 (21), 91 (100), 77 (78), 65 (37). HRMS
calcd. for C13H16N4O2, 260.1273, found 260.1270.
In conclusion, a new 1,3-dipolar cycloaddition for the effective
synthesis of 5-amino-1,2,4-triazoles has been developed by
treating symmetric or asymmetric carbodiimides with function-
alized hydrazonoyl hydrochlorides in the presence of triethyl-
amine as a base. Among the variously employed carbodimides,
only diphenyl carbodiimide failed to serve as a substrate for the
newly developed reaction. Further mechanistic studies suggest
that the alkyl moieties of the carbodiimides function as suitable
leaving groups able to readily depart from the 4,5-dihydro-5-
imino-1,2,4-triazole intermediate thus forming the correspond-
ing carbocations. Such carbocations can then be trapped by
triethylamine to generate the quaternary triethyl alkylammo-
nium chloride salt. This proposed mechanism is supported by
the isolation and characterization of the ammonium salt. Fur-
ther, the relative reactivity of asymmetric and symmetric carbo-
diimides was found to be consistent with the stability of subse-
quently formed carbocations; tert-butyl > cyclopentyl > iso-
propyl > cyclohexyl > ethyl >> phenyl.
Methyl 1-p-Tolyl-5-(isopropylamino)-1H-1,2,4-triazole-3-carb-
oxylate (3b): Yellow solid; m.p. 185–189 °C. 1H NMR (200 MHz,
CDCl3): δ = 0.98 (d, J = 6.8 Hz, 3 H, CH3), 1.33 (d, J = 6.8 Hz, 3 H,
CH3), 2.15 (s, 3 H, CH3), 3.59 (sep, J = 6.8 Hz, 1 H), 3.99 (s, 3 H, OCH3),
6.76 (d, J = 8.3 Hz, 2 H, ArH), 6.93 (d, J = 8.3 Hz, 2 H, ArH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 20.57, 22.47, 29.64, 45.36, 52.81, 114.91
(2 × CH), 115.92, 129.93 (2 × CH), 131.29, 136.03, 136.94,
159.49 ppm. IR (KBr): ν = 2926 (m), 1730 (s, C=O), 1614 (m), 1469
˜
(m), 1325 (m), 1255 (s, C–O), 1132 (m), 736 (m) cm–1. EIMS: m/z
(%) = 274 (27) [M]+, 243 (25), 242 (22), 233 (40), 232 (100), 211 (47),
132 (29), 119 (22), 105 (41), 91(93). HRMS calcd. for C14H18N4O2,
274.1430, found 274.1436.
Methyl 1-[4-(Trifluoromethyl)phenyl]-5-(isopropylamino)-1H-
1,2,4-triazole-3-carboxylate (3c): Yellow solid; m.p. 164–168 °C. 1H
NMR (200 MHz, CDCl3): δ = 1.02 (d, J = 6.8 Hz, 3 H, CH3), 1.35 (d,
J = 6.8 Hz, 3 H, CH3), 3.60 (sep, J = 6.8 Hz, 1 H), 3.99 (s, 3 H, OCH3),
6.88 (d, J = 8.6 Hz, 2 H, ArH), 7.40 (d, J = 8.6 Hz, 2 H, ArH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 20.74, 22.42, 29.70, 45.79, 53.24, 114.36,
115.07, 121.53, 123.54 (CF3), 124.20 (CF3), 124.85 (CF3), 124.91 (CF3),
Experimental Section
126.47, 126.90, 137.68, 141.55, 159.14 ppm. IR (KBr): ν = 2926 (m),
˜
General: All chemicals were reagent grade and used as purchased.
All reactions were carried out under nitrogen atmosphere and mon-
itored by TLC analysis. Flash column chromatography was carried
out on silica gel (230–400 mesh). Commercially available reagents
were used without further purification unless otherwise noted. 1H
1734 (s, C=O), 1616 (m), 1483 (m), 1315 (m), 1259 (s, C–O), 1126
(m), 738 (m), 592 (m) cm–1. EIMS: m/z (%) = 328 (27) [M]+, 297(48),
286(100), 265(66), 212(29), 186(48), 159(23), 145(82). HRMS calcd.
for C14H15F3N4O2, 328.1147, found 328.1142.
NMR were recorded at 200, 400, or 500 MHz and 13C NMR were Methyl 1-(4-Fluorophenyl)-5-(isopropylamino)-1H-1,2,4-
recorded at 50, 100, or 125 MHz, respectively, in CDCl3, CH3OD, and
[D6]DMSO as solvents. The standard abbreviations s, d, t, q, and m
refer to singlet, doublet, triplet, quartet, and multiplet, respectively.
Coupling constant (J), whenever discernible, have been reported in
Hz. Infrared spectra (IR) were recorded as neat solutions or solids;
and mass spectra were recorded using electron impact or electro-
triazole-3-carboxylate (3d): Yellow solid; m.p. 149–153 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.01 (d, J = 7.0 Hz, 3 H, CH3), 1.34 (d, J =
7.0 Hz, 3 H, CH3), 3.55 (sep, J = 7.0 Hz, 1 H), 3.96 (s, 3 H, OCH3),
6.79–6.87 (m, 4 H, ArH) ppm. 13C NMR (125 MHz, CDCl3): δ = 20.65,
22.47, 45.59, 52.99, 115.72, 115.90, 115.96, 116.30, 116.36, 135.52,
136.55, 157.37, 159.36 ppm. IR (KBr): ν = 3410 (m), 2924 (m), 1732
˜
spray ionization techniques. The wavenumbers reported are refer- (s, C=O), 1546 (m), 1473 (m), 1323 (m), 1257 (s, C–O), 1122 (m), 744
enced to the polystyrene 1601 cm–1 absorption. Flash column chro-
matography purification of compounds was carried out by gradient
elution using hexanes in ethyl acetate (EA) unless otherwise stated.
(m) cm–1. EIMS: m/z (%) = 278 (20) [M]+, 247 (67), 236 (79), 230 (31),
215 (64), 162 (26), 136 (61), 123 (47), 109 (97), 95 (100), 83 (28).
HRMS calcd. for C13H15FN4O2, 278.1179, found 278.1184.
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Methyl 1-(4-Chlorophenyl)-5-(isopropylamino)-1H-1,2,4-
triazole-3-carboxylate (3e): Yellow solid; m.p. 198–202 °C. 1H NMR
(200 MHz, CDCl3): δ = 1.02 (d, J = 6.8 Hz, 3 H, CH3), 1.34 (d, J =
6.8 Hz, 3 H, CH3), 3.55 (sep, J = 6.8 Hz, 1 H), 3.97 (s, 3 H, OCH3), 6.75
(d, J = 9.2 Hz, 2 H, ArH), 7.11 (d, J = 9.2 Hz, 2 H, ArH) ppm. 13C NMR
(50 MHz, CDCl3): δ = 20.70, 22.44, 45.63, 53.07, 115.87, 116.01 (2 ×
CH), 127.30, 129.16 (2 × CH), 136.85, 137.66, 159.23 ppm. IR (KBr):
160.74, 164.81 ppm. IR (KBr): ν = 3332 (m), 2964 (m), 1732 (s, C=O),
˜
1556 (m), 1392 (m), 1219 (s, C–O), 1153 (m), 840 (m), 729 (m) cm–1
.
EIMS: m/z (%) = 292 (13) [M]+, 236 (100), 176 (24), 109 (57), 95 (22),
57 (21). HRMS calcd. for C14H17N4O2, 292.1336, found 292.1334.
Methyl 1-(4-Chlorophenyl)-5-(tert-butylamino)-1H-1,2,4-
triazole-3-carboxylate (4e): Yellow solid; m.p. 150–154 °C. 1H NMR
(200 MHz, CDCl3): δ = 1.41 (s, 9 H, tert-butyl), 3.91 (s, 3 H, OCH3),
4.21 (s,1 H, NH), 7.38–7.49 (m, 4 H, ArH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 29.07, 29.54, 50.09, 52.52, 53.03, 125.74 (2 × CH), 130.13
ν = 2953 (m), 1732 (s, C=O), 1595 (m), 1469 (m), 1323 (m), 1257 (s,
˜
C–O), 1130 (m), 821 (m), 678 (m) cm–1. EIMS: m/z (%) = 294 (34)
[M]+, 280 (22), 263 (56), 252(100), 233 (24), 231 (63), 178 (23), 152
(48), 139 (35), 125 (77), 113 (25), 111 (76), 105 (20). HRMS calcd. for
C13H15ClN4O2, 294.0884, found 294.0880.
(2 × CH), 134.69, 152.25, 154.03, 156.98, 160.76 ppm. IR (KBr): ν =
˜
3361 (m), 2964 (m), 1732 (s, C=O), 1556 (m), 1392 (m), 1215 (s, C–
O), 1141 (m), 842 (m), 738 (m) cm–1. EIMS: m/z (%) = 308 (11) [M]+,
254 (24), 252 (76), 125 (29). HRMS calcd. for C14H17ClN4O2, 308.1040,
found 308.1037.
Methyl 1-(4-Methoxyphenyl)-5-(isopropylamino)-1H-1,2,4-
triazole-3-carboxylate (3f): Yellow solid; m.p. 163–167 °C. 1H NMR
(200 MHz, CDCl3): δ = 0.98 (d, J = 6.8 Hz, 3 H, CH3), 1.33 (d, J =
6.8 Hz, 3 H, CH3), 3.57 (sep, J = 7.0 Hz, 1 H), 3.66 (s, 3 H, OCH3), 3.94
(s, 3 H, OCH3), 6.69 (d, J = 9.4 Hz, 2 H, ArH), 6.81 (d, J = 9.4 Hz, 2 H,
ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 20.63, 22.49, 29.64, 45.40,
52.77, 55.26, 114.32 (2 × CH), 116.27 (2 × CH), 133.16, 135.84,
Methyl 1-(4-Methoxyphenyl)-5-(tert-butylamino)-1H-1,2,4-tria-
zole-3-carboxylate (4f): Yellow solid; m.p. 126–128 °C. 1H NMR
(200 MHz, CDCl3): δ = 1.41 (s, 9 H, tert-butyl), 3.82 (s, CH3), 3.92 (s,
3 H, OCH3), 4.14 (s, 1 H, NH), 6.98 (d, J = 8.0 Hz, 2 H, ArH), 7.34 (d,
J = 8.0 Hz, 2 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 29.14 (3 ×
CH), 29.64, 52.49, 53.72, 55.55, 114.97 (2 × CH), 126.47 (2 × CH),
154.86, 159.49 ppm. IR (KBr): ν = 2924 (m), 1732 (s, C=O), 1462 (m),
˜
1327 (m), 1265 (s, C–O), 1130 (m), 740 (s) cm–1. EIMS: m/z (%) = 290
(32) [M]+, 258 (22), 248 (100), 227 (34), 163 (25), 149 (34), 135 (51),
121 (62), 107 (92), 77 (23). HRMS calcd. for C14H18N4O3, 290.1379,
found 290.1372.
128.51, 151.73, 154.31, 159.92, 160.97 ppm. IR (KBr): ν = 3342 (m),
˜
2960 (m), 1732 (s, C=O), 1568 (m), 1479 (m), 1392 (m), 1217 (s, C–
O), 1147 (m), 835 (m), 731 (m) cm–1. EIMS: m/z (%) = 304 (18) [M]+,
248 (100), 135 (23), 121 (39). HRMS calcd. for C15H20N4O3, 304.1535,
found 304.1531.
Methyl 1-Phenyl-5-(tert-butylamino)-1H-1,2,4-triazole-3-carb-
oxylate (4a): Yellow solid; m.p. 105–107 °C. 1H NMR (200 MHz,
CDCl3): δ = 1.39 (s, 9 H, tert-butyl), 3.89 (s, 3 H, OCH3), 4.30 (s, 1 H,
NH), 7.37–7.50 (m, 5 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ =
29.05 (3 × CH), 52.38, 52.80, 124.42 (2 × CH), 128.90, 129.86 (2 ×
Methyl 1-Phenyl-5-(cyclohexylamino)-1H-1,2,4-triazole-3-carb-
oxylate (5a): Yellow solid; m.p. 148–152 °C. 1H NMR (200 MHz,
CDCl3): δ = 0.76–1.78 (m, 11 H, cyclohexyl), 3.25–3.37 (m, 1 H, NH),
3.94 (s, 3 H, OCH3), 6.80–6.86 (m, 3 H, ArH), 7.06–7.04 (m, 2 H,
ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 24.56, 24.97, 26.29, 29.58,
29.74, 32.56, 52.83, 54.55, 114.98 (2 × CH), 115.83, 121.87, 128.82
CH), 136.02, 151.98, 154.00, 160.85 ppm. IR (KBr): ν = 3342 (m), 2964
˜
(m), 1732 (s, C=O), 1568 (m), 1479 (m), 1315 (m), 1215 (s, C–O), 1145
(m), 761 (m), 696 (m) cm–1. EIMS: m/z (%) = 274 (14) [M]+, 218
(100), 91 (28), 77 (22). HRMS calcd. for C14H18N4O2, 274.1430, found
274.1437.
(2 × CH), 136.36, 139.16, 159.56 ppm. IR (KBr): ν = 3441 (m), 2929
˜
(m), 1732 (s, C=O), 1600 (m), 1469 (m), 1319 (m), 1257 (s, C–O), 1118
(m), 748 (m), 690 (m) cm–1. EIMS: m/z (%) = 300 (6) [M]+, 294 (29),
287 (28), 229 (79), 219 (97), 197 (86), 144 (44), 118 (54), 91 (54), 77
(100), 55 (83). HRMS calcd. for C16H20N4O2, 300.1586, found
Methyl 1-p-Tolyl-5-(tert-butylamino)-1H-1,2,4-triazole-3-carb-
oxylate (4b): Yellow solid; m.p. 130–132 °C. 1H NMR (200 MHz,
CDCl3): δ = 1.42 (s, 9 H, tert-butyl), 2.39 (s, CH3), 3.93 (s, 3 H, OCH3), 300.1584.
4.23 (s, 1 H, NH), 7.25–7.35 (m, 5 H, ArH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 21.17, 29.16 (3 × CH), 52.45, 52.79, 124.50 (2 × CH),
Methyl 1-p-Tolyl-5-(cyclohexylamino)-1H-1,2,4-triazole-3-carb-
oxylate (5b): Yellow solid; m.p. 234–238 °C. 1H NMR (200 MHz,
CDCl3): δ = 0.89–1.73 (m, 11 H, cyclohexyl), 2.13 (s, 3 H, CH3), 3.22–
3.34 (m, 1 H, NH), 3.94 (s, 3 H, OCH3), 6.73 (d, J = 8.6 Hz, 2 H, ArH),
6.91 (d, J = 8.6 Hz, 2 H, ArH) ppm. 13C NMR (125 MHz, CDCl3): δ =
20.53, 25.08, 26.37, 26.44, 29.85, 32.59, 52.81, 54.55, 115.02 (2 × CH),
115.62, 129.49 (2 × CH), 131.19, 136.01, 136.96, 159.71 ppm. IR (KBr):
130.47 (2 × CH), 133.46, 139.23, 154.15, 160.98 ppm. IR (KBr): ν =
˜
3340 (m), 2924 (m), 1732 (s, C=O), 1568 (m), 1477 (m), 1369 (m),
1217 (s, C–O), 1145 (m), 821 (m), 729 (m) cm–1. EIMS: m/z (%) = 288
(15) [M]+, 232 (100), 105 (40), 91 (18). HRMS calcd. for C15H20N4O2,
288.1586, found 288.1588.
Methyl 1-[4-(Trifluoromethyl)phenyl]-5-(tert-butylamino)-1H-
1,2,4-triazole-3-carboxylate (4c): Yellow solid; m.p. 148–150 °C. 1H
NMR (200 MHz, CDCl3): δ = 1.45 (s, 9 H, tert-butyl), 3.94 (s, 3 H,
OCH3), 4.23 (s, 1 H, NH), 7.65 (d, J = 8.0 Hz, 2 H, ArH), 7.77 (d, J =
8.0 Hz, 2 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 29.07 (3 ×
CH), 29.56, 52.63, 53.27, 124.20 (2 × CH), 127.16 (2 × CH), 131.44
(CF3), 132.18 (CF3), 132.77 (CF3), 133.82 (CF3), 139.25, 152.62, 154.00,
ν = 3286 (m), 2929 (m), 1730 (s, C=O), 1614 (m), 1469 (m), 1317 (m),
˜
1259 (s, C–O), 1116 (m), 736 (m) cm–1. EIMS: m/z (%) = 313 (11)
[M]+, 301 (22), 273 (20), 258 (23), 243 (45), 233 (64), 211 (57), 158
(31), 105 (46), 91 (100), 55 (44). HRMS calcd. for C17H22N4O2,
314.1743, found 314.1748.
Methyl 1-[4-(Trifluoromethyl)phenyl]-5-(cyclohexylamino)-1H-
1,2,4-triazole-3-carboxylate (5c): Yellow solid; m.p. 174–178 °C. 1H
NMR (200 MHz, CDCl3): δ = 0.82–1.84 (m, 11 H, cyclohexyl), 3.27–
3.39 (m, 1 H, NH), 3.99 (s, 3 H, OCH3), 6.85 (d, J = 8.6 Hz, 2 H, ArH),
7.38 (d, J = 8.6 Hz, 2 H, ArH) ppm. 13C NMR (125 MHz, CDCl3): δ =
24.96, 26.31 (2 × CH), 29.67, 30.03, 32.65, 53.20, 54.89, 114.43 (2 ×
CH), 114.71, 123.13 (CF3), 123.63 (CF3), 123.89 (CF3), 124.01 (CF3),
160.69 ppm. IR (KBr): ν = 3329 (m), 2964 (m), 1732 (s, C=O), 1571
˜
(m), 1481 (m), 1369 (m), 1220 (s, C–O), 1130 (m), 846 (m), 727
(m) cm–1. EIMS: m/z (%) = 342 (12) [M]+, 286 (100), 226 (18), 159 (18),
57 (17). HRMS calcd. for C15H17F3N4O2, 342.1304, found 342.1307.
Methyl 1-(4-Fluorophenyl)-5-(tert-butylamino)-1H-1,2,4-
triazole-3-carboxylate (4d): Yellow solid; m.p. 1 40–142 °C. 1H NMR
(200 MHz, CDCl3): δ = 1.38 (s, 9 H, tert-butyl), 3.88 (s, 3 H, OCH3),
4.19 (s, 1 H, NH), 7.17 (t, J = 6.0 Hz, 2 H, ArH), 7.38–7.45 (m, 2 H,
ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 29.02 (3 × CH), 52.49,
126.35, 126.37, 137.65, 141.56, 159.33 ppm. IR (KBr): ν = 3290 (m),
˜
2929 (m), 1732 (s, C=O), 1614 (m), 1454 (m), 1317 (m), 1265 (s, C–
O), 1114 (m), 740 (m) cm–1. EIMS: m/z (%) = 368 (6) [M]+, 297 (91),
287 (80), 265 (80), 212 (51), 186 (47), 145 (67), 83 (43), 55 (100).
52.87, 116.68, 117.14, 126.66, 126.83, 131.98, 152.02, 154.13, 159.84, HRMS calcd. for C17H19F3N4O2, 368.1460, found 368.1466.
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Full Paper
Methyl 1-(4-Fluorophenyl)-5-(cyclohexylamino)-1H-1,2,4-
triazole-3-carboxylate (5d): Yellow solid; m.p. 201–205 °C. 1H NMR
δ = 53.94, 111.91, 113.03, 113.39, 114.10, 117.69, 121.61, 122.49,
124.40, 125.05, 126.37, 129.44, 132.22, 132.76, 138.64, 145.62,
(200 MHz, CDCl3): δ = 0.83–1.76 (m, 11 H, cyclohexyl), 3.22–3.34 (m, 160.81 ppm. IR (KBr): ν = 3344 (m), 2924 (m), 1716 (s, C=O), 1616
˜
1 H, NH), 3.93 (s, 3 H, OCH3), 6.76–6.81 (m, 4 H, ArH) ppm. 13C NMR
(50 MHz, CDCl3): δ = 25.55, 26.31 (2 × CH), 29.62, 32.58, 52.94, 54.65,
115.43, 115.87, 116.25, 116.40, 135.45, 136.44, 155.79, 159.46,
(m), 1435 (m), 1246 (s, C–O), 1064 (m), 748 (m) cm–1. EIMS: m/z
(%) = 362 (4) [M]+, 230 (34), 206 (100), 145 (24), 135 (24), 118 (24),
93 (28), 77 (37). HRMS calcd. for C17H13F3N4O2, 362.0991, found
160.58 ppm. IR (KBr): ν = 3446 (m), 2929 (m), 1732 (s, C=O), 1600 362.0990.
˜
(m), 1454 (m), 1317 (m), 1265 (s, C–O), 1134 (m), 738 (m) cm–1. EIMS:
Methyl 1-(4-Fluorophenyl)-5-(phenylamino)-1H-1,2,4-triazole-3-
m/z (%) = 318 (4) [M]+, 247 (53), 237 (55), 215 (45), 136 (44), 123
(44), 111 (42), 109 (58), 97 (51), 95 (77), 83 (69), 81, (46), 71 (52),
57 (78), 55 (100). HRMS calcd. for C16H19FN4O2, 318.1492, found
318.1495.
carboxylate (6d): Brown solid; m.p. 84–86 °C. 1H NMR (200 MHz,
CDCl3): δ = 3.86 (s, 3 H, OCH3), 6.06 (d, J = 6 Hz, 1 H, phenyl), 6.32–
6.37 (m, 1 H, phenyl), 6.32–6.37 (m, 1 H, phenyl), 6.58–7.74 (m, 2 H,
phenyl), 7.03–7.12 (m, 3 H, ArH), 7.32–7.39 (m, 2 H, ArH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 53.37, 112.34, 113.33, 115.93, 116.38,
124.27, 126.06, 126.23, 129.02, 131.68, 133.62, 137.42, 139.49,
Methyl 1-(4-Chlorophenyl)-5-(cyclohexylamino)-1H-1,2,4-
triazole-3-carboxylate (5e): Brown solid; m.p. 193–197 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.04–1.72 (m, 11 H, cyclohexyl), 3.09 (t, J = 158.09, 160.81, 162.96 ppm. IR (KBr): ν = 3332 (m), 2920 (m), 1732
˜
12.0 Hz, 1 H, NH), 3.97 (s, 3 H, OCH3), 6.73 (d, J = 9.0 Hz, 2 H, ArH),
(s, C=O), 1600 (m), 1435 (m), 1219 (s, C–O), 1014 (m), 752 (m) cm–1
EIMS: m/z (%) = 285 (100, M+ – 27), 224 (92), 194 (91), 133 (68), 105
.
7.09 (d, J = 9.0 Hz, 2 H, ArH) ppm. 13C NMR (125 MHz, CDCl3): δ =
25.01, 26.33, 26.37, 29.94, 32.67, 53.07, 54.78, 115.12, 116.09 (2 × (44), 95 (47), 91 (85), 77 (37). HRMS calcd. for C16H13FN4O2, 312.1023,
CH), 127.20, 129.97 (2 × CH), 136.83, 137.67, 159.43 ppm. IR (KBr):
found 312.1019.
ν = 3290 (m), 2931 (m), 1732 (s, C=O), 1593 (m), 1465 (m), 1319 (m),
˜
Methyl 1-(4-Chlorophenyl)-5-(phenylamino)-1H-1,2,4-triazole-
3-carboxylate (6e): Brown solid; m.p. 165–169 °C. 1H NMR
(500 MHz, CDCl3): δ = 3.87 (s, 3 H, OCH3), 6.23 (d, J = 8.0 Hz, 1 H,
phenyl), 6.37 (d, J = 7.5 Hz, 1 H, phenyl), 6.63–6.73 (m, 2 H, phenyl),
7.32–7.36 (m, 5 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 53.39,
112.51, 113.62, 114.98, 117.12, 124.31, 124.53, 124.59, 129.18,
129.34, 130.32, 132.11, 132.74, 137.94, 141.67, 160.82 ppm. IR (KBr):
1246 (s, C–O), 1111 (m), 736 (m) cm–1. EIMS: m/z (%) = 334 (13)
[M]+, 287 (26), 270 (25), 263 (79), 253 (52), 231 (87), 178 (29), 152
(83), 135 (68), 125 (58), 111 (63), 83 (42), 55 (100). HRMS calcd. for
C16H19ClN4O2, 334.1197, found 334.1200.
Methyl 1-(4-Methoxyphenyl)-5-(cyclohexylamino)-1H-1,2,4-
triazole-3-carboxylate (5f): Yellow solid; m.p. 120–122 °C. 1H NMR
(200 MHz, CDCl3): δ = 0.77–1.70 (m, 11 H, cyclohexyl), 3.18–3.20 (m, ν = 3348 (m), 2927 (m), 1739 (s, C=O), 1589 (m), 1435 (m), 1265 (s,
˜
1 H, NH), 3.58 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 6.62 (d, J = 9.2 Hz,
2 H, ArH), 6.74 (d, J = 9.2 Hz, 2 H, ArH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 25.46, 29.50, 30.60, 32.47, 34.73, 52.65, 54.42, 55.04,
114.05 (2 × CH), 115.78, 116.29 (2 × CH), 132.99, 135.65, 154.63,
C–O), 1053 (m), 744 (m) cm–1. EIMS: m/z (%) = 301 (33) [M+ – 27],
206 (100), 194 (26), 91 (20). HRMS calcd. for C16H13ClN4O2, 328.0727,
found 328.0729.
159.53 ppm. IR (KBr): ν = 3305 (m), 2929 (m), 1730 (s, C=O), 1514
˜
(m), 1454 (m), 1317 (m), 1246 (s, C–O), 1130 (m), 736 (m) cm–1. EIMS:
m/z (%) = 330 (5) [M]+, 248 (38), 227 (33), 135 (42), 121 (97), 107
(100), 55 (44). HRMS calcd. for C17H22N4O3, 330.1692, found
330.1696.
Acknowledgments
The authors are grateful to the China Medical University
(CMU104-S-49) and the Tsuzuki Institute for Traditional Medi-
cine for financial support. Prof. Cheng-Tung Lin and Ding-Yah
Yang are thanked for kindly revising the manuscript.
Methyl 1-Phenyl-5-(phenylamino)-1H-1,2,4-triazole-3-carboxyl-
ate (6a): Brown solid; m.p. 84–86 °C. 1H NMR (200 MHz, CDCl3): δ =
1.24 (s, 5 H, phenyl), 3.91 (s, 3 H, OCH3), 7.65–7.76 (m, 5 H, ArH),
8.34 (s, 1 H, NH) ppm. 13C NMR (50 MHz, CDCl3): δ = 29.33, 29.66,
53.46, 114.49 (2 × CH), 119.70, 128.35, 128.60, 128.95, 129.45,
Keywords: Cycloaddition · Regioselectivity · Nitrogen
heterocycles · Carbodiimide · Nitrilimines
131.51, 132.13, 132.34, 133.75, 141.45, 160.17 ppm. IR (KBr): ν =
˜
3275 (m), 2924 (m), 1728 (s, C=O), 1604 (m), 1435 (m), 1230 (s, C–
O), 1026 (m), 713 (m) cm–1. EIMS: m/z (%) = 294 (100) [M]+, 293
(60), 185 (51), 183 (69), 93 (25). HRMS calcd. for C16H14N4O,
294.1117, found 294.1114.
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Methyl 1-p-Tolyl-5-(phenylamino)-1H-1,2,4-triazole-3-carboxyl-
1
ate (6b): Brown solid; m.p. 144–146 °C. H NMR (200 MHz, CDCl3):
δ = 2.33 (s, 3 H, CH3), 3.85 (s, 3 H, OCH3), 6.09–6.34 (m, 3 H, phenyl),
6.54–6.71 (m, 2 H, phenyl), 7.13–7.29 (m, 5 H, ArH) ppm. 13C NMR
(125 MHz, CDCl3): δ = 52.89, 112.56, 113.20, 113.85, 116.78, 121.71,
124.05, 124.09, 124.15, 126.64, 129.32, 129.74, 129.91, 131.33,
139.51, 140.58, 163.91 ppm. IR (KBr): ν = 3352 (m), 2920 (m), 1739
˜
(s, C=O), 1604 (m), 1435 (m), 1257 (s, C–O), 1006 (m), 756 (m) cm–1
.
EIMS: m/z (%) = 281 (77) [M+ – 27], 270 (27), 230 (100), 214 (47), 206
(95), 152 (54), 135 (76), 91 (20), 77 (25). HRMS calcd. for C17H16N4O2,
308.1273, found 308.1276.
Methyl 1-[4-(Trifluoromethyl)phenyl]-5-(phenylamino)-1H-
1,2,4-triazole-3-carboxylate (6c): Brown solid; m.p. 64–66 °C. 1H
NMR (200 MHz, CDCl3): δ = 3.93 (s, 3 H, OCH3), 6.95–7.12 (m, 4 H,
phenyl), 7.45–7.54 (m, 5 H, ArH) ppm. 13C NMR (125 MHz, CDCl3):
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Eur. J. Org. Chem. 2016, 2328–2335
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Received: March 2, 2016
Published Online: April 13, 2016
Eur. J. Org. Chem. 2016, 2328–2335
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim