A convenient synthesis of 4,5-disubstituted 1,2,4-triazoles functionalized in position 3

Article abstract of DOI:10.1055/s-2005-921754

A convenient approach to 4,5-disubstituted 3-hydroxymethyl-1,2,4-triazoles as well as to the corresponding 3-chloromethyl and 3-carboxaldehyde derivatives was developed starting from 3-mercapto-1,2,4-triazoles which can, in turn, be readily obtained from

Full text of DOI:10.1055/s-2005-921754

156
PAPER
A Convenient Synthesis of 4,5-Disubstituted 1,2,4-Triazoles Functionalized
in Position 3
C
onvenient Synthe
a
sis of 4,5-D
t
isubst
a
itute
d
1,2,4
l
-Triazo
i
les a V. Ivanova,a Sergey I. Sviridov,*b Sergey V. Shorshnev,b Aleksander E. Stepanova
a
M. V. Lomonosov Moscow State Academy of Fine Chemical Technology, Malaya Pirogovskaya 1, 119435 Moscow, Russia
ChemBridge Corporation, Malaya Pirogovskaya 1, 119435 Moscow, Russia
Fax +7(95)9564948; E-mail: sviridov@chembridge.ru
b
Received 28 April 2005; revised 4 July 2005
N
N
N
N
Abstract: A convenient approach to 4,5-disubstituted 3-hydroxy-
methyl-1,2,4-triazoles as well as to the corresponding 3-chloro-
methyl and 3-carboxaldehyde derivatives was developed starting
from 3-mercapto-1,2,4-triazoles which can, in turn, be readily ob-
tained from acyl hydrazines and isothiocyanates.
H2O2–AcOH
CH2Cl2
R1
R1
SH
N
N
R2
R2
1a–d
2a–d
Key words: alcohols, aldehydes, heterocycles, oxidations, 1,2,4-
triazoles
(CH2O)n, 110 °C xylene
N
N
SOCl2, Py
CH2Cl2
N
N
Cl
OH
R1
R1
N
The triazole fragment is often included into a structure if
new biologically active compounds are designed.1 The
method for their synthesis is determined to a great extent
by the set of substituents in the triazole ring. Preparation
of 3,4,5-trisubstituted triazoles is usually based on the cy-
clization of readily available diacylhydrazines or recy-
clization of the corresponding 1,3,4-oxadiazoles.2
However, this approach often requires an application of
high temperatures3 and/or strongly acidic reagents, which
can considerably restrict the choice of the substituents.
N
R2
R2
3a–d
4a–d
benzene
MnO2
N
N
R1
CHO
N
R2
5a–d
a R1 = R2 = Me; b R1 = Me, R2 = Ph; c R1 = Ph, R2 = Me; d R1 = R2 = Ph
We report here a convenient approach to 4,5-disubstituted
1,2,4-triazoles bearing some functional groups in position
3 starting from the corresponding 3-mercapto-1,2,4-tri-
azoles (Scheme 1).
Scheme 1
into position 3 in the literature.3,5 We used heating with
paraformaldehyde in xylene as the main method. Howev-
er, in the case of 4,5-dimethyl-1,2,4-triazole (2a), the
yield turned out to be rather low due to formation of diol
6 as a by-product (Scheme 2). This compound formed
upon nucleophilic attack of formaldehyde to the 5-methyl
group of triazole 2a, since this group is a weak CH-acid.
Minor products formed due to addition of three and even
four formaldehyde molecules to 2a could be observed
upon LCMS analysis of a crude reaction mixture. Replac-
ing the aprotic medium with aqueous formalin and, as a
The synthesis of 3-mercapto-1,2,4-triazoles 1 from readi-
ly available acylhydrazines and isothiocyanates is well
known,2 which makes them attractive intermediates for
the synthesis of 3,4,5-trisubstituted derivatives of triazole.
Removing the mercapto group is required as the first
stage, which can be attained by oxidation. In order to de-
velop a general method, simple 1,2,4-triazoles 1a–d were
chosen, in which all the four combinations of aromatic
and aliphatic substituents in positions 4 and 5 were
present. We modified a known method,4 according to
which we obtained triazoles unsubstituted in position 3
(2a–d, Table 1) using 30% H2O2 in a CH2Cl2–AcOH mix-
ture.
Table 1 Synthesis of Derivatives of Triazoles 2–5
R1
R2
2
Yield, 3
(%)
Yield, 4
(%)
Yield, 5
(%)
Yield
(%)
Hydroxymethylation of 1,2,4-triazoles 2a–d is a key stage
of our approach. It was shown that triazoles easily under-
go condensation with formaldehyde under neutral condi-
tions, which gave alcohols 3a–d in good yields (Table 1).
This reaction was studied very little, and there are only
single examples of hydroxymethylation of 1,2,4-triazoles
Me
Me
Ph
Me
Ph
a
b
c
81
83
83
86
a
b
c
50a
90
96
81
a
b
c
21b
75
88
96
a
b
c
94
77
71
75
Me
Ph
Ph
d
d
d
d
a Yield of alcohol in an aqueous solution at 90 °C: 73%.
b Yield of hydrochloride according to alternative procedure: 96%.
SYNTHESIS 2006, No. 1, pp 0156–0160
Advanced online publication: 16.12.2005
0
6
.
0
1
.2
0
0
6
DOI: 10.1055/s-2005-921754; Art ID: T05405SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Convenient Synthesis of 4,5-Disubstituted 1,2,4-Triazoles
157
d6. Mass spectra were obtained using Kratos MS-30 apparatus. IR
spectra were recorded on an EQUNOX 55 IR-Fourier spectrometer
made by Bruker. Elemental analyses (C, H, N) were carried out on
automatic 1106 and 1500 analyzers made by CARLO-ERBA (Ita-
ly); the Cl content was determined by the classic Sheniger method
of titrimetric determination of halogens.
N
N
2a
N
(CH2O)n, 110 °C
xylene
Compounds 1a–d were obtained according to procedures published
in the literature.4,8–11 All the other starting materials were obtained
from commercial suppliers and were used without further purifica-
tion.
N
N
N
N
OH
OH
HO
+
N
N
50%
50%
Oxidation of 3-Mercapto-1,2,4-triazoles; General Procedure
A solution of starting 3-mercapto-1,2,4-triazole 1 (0.18 mol) in
CH2Cl2 (350 mL) was cooled to 0 °C, and a 30% aq solution of H2O2
(0.40 mol) in AcOH (270 mL) was added in portions under cooling
and stirring. Then the ice bath was removed, and the stirring was
continued at r.t. for 3 h (TLC on silica gel; CHCl3–MeOH, 9:1). The
reaction mixture was alkalized under cooling with NaOH to pH 10.
The organic layer was separated, and the aqueous one was washed
with CH2Cl2 (2 × 100 mL). The combined extracts were dried with
Na2SO4 and evaporated. The residue was purified by column chro-
matography (CHCl3–MeOH, 100:0 → 70:30). In the case of product
2a, the reaction mixture was evaporated to dryness before the alka-
lization, and the residue was distilled at r.t. under high vacuum.
6
3a
Scheme 2
result, decreasing the reaction temperature enabled to in-
crease considerably the yield of required product 3a.
In order to synthesize target structures displaying biolog-
ical activity, alcohols 3 themselves can be used. However,
it would be preferable to transform them into derivatives
with more active functional groups. Thus, a number of ex-
amples for the preparation of 3-chloromethyl-1,2,4-tri-
azoles, e.g., by acylation of amidrazones with
chloroacetyl chloride was described in the literature,6 but
using corresponding hydroxymethyl precursors3,5 seems
to be more convenient. We also carried out transformation
of the obtained alcohols 3a–d into 3-chloromethyl deriv-
atives 4a–d under the action of SOCl2. The obtained prod-
ucts 4a–d are rather stable, even as bases, and can be
stored for several months virtually without decomposi-
tion. In the case of compound 4a, the yield turned out to
be low. However, using an alternative approach affording
hydrochloride of the required product gave an excellent
result.
3,4-Dimethyl-4H-1,2,4-triazole (2a)12
Yield: 81%; light-yellow crystals; mp 38–40 °C.
IR (KBr): 3109, 1650, 1536, 1443, 1396, 1200, 1069, 724, 648
cm–1.
1H NMR: d = 2.31 (s, 3 H, CH3), 3.55 (s, 3 H, CH3), 8.31 (s, 1 H,
CH).
13C NMR: d = 9.5, 30.2, 144.5, 150.7.
MS–EI: m/z (Irel) = 97 (80) [M+], 56 (30).
Anal. Calcd for C4H7N3·0.2 M H2O (100.72): C, 47.70; H, 7.41; N,
41.72. Found: C, 47.78; H, 7.20; N, 41.69.
Due to the hygroscopic nature of the product, no correct elemental
analysis was possible.
Oxidation of alcohols 3a–d with MnO2 resulted in the cor-
responding aldehydes 5a–d (Scheme 1) in good yields
3-Methyl-4-phenyl-4H-1,2,4-triazole (2b)4,10,13
(Table 1). It is noteworthy that analogous 3-formyl-1,2,4- Yield: 83%; white crystals; mp 112–113 °C.
triazoles were synthesized previously by ring opening of
their precursors, 1,4-diazepines.7 It is important to take
into account that any contact with alcohols should be
avoided when working with these aldehydes 5a–d, be-
cause the latter form very readily hemiacetals and then ac-
etals.
IR (KBr): 3050, 1653, 1625, 1595, 1500, 1394, 1310, 950, 770, 700,
695 cm–1.
1H NMR: d = 2.34 (s, 3 H, CH3), 7.50–7.59 (m, 5 H, Ph), 8.66 (s, 1
H, CH).
13C NMR: d = 10.5, 125.3, 128.9, 129.8, 134.2.
MS–EI: m/z (Irel) = 159 (100) [M+], 118 (82), 91 (98), 77 (82), 64
In summary, we developed a convenient method for the
preparation of 4,5-disubstituted 1,2,4-triazoles containing
active functional groups in position 3 starting from readily
available acylhydrazines and isothiocyanates. It was
shown that 1,2,4-triazoles with free position 3 readily un-
dergo hydroxymethylation at this position under neutral
conditions. The obtained alcohols can be readily trans-
formed into the corresponding alkyl chlorides and alde-
hydes. The suggested reactions proceed under rather mild
(35), 51 (50).
Anal. Calcd for C9H9N3 (159.19): C, 67.91; H, 5.70; N, 26.40.
Found: C, 67.74; H, 5.61; N, 26.61.
4-Methyl-3-phenyl-4H-1,2,4-triazole (2c)14
Yield: 83%; white crystals; mp 115–117 °C.
IR (KBr): 3089, 2960, 1512, 1442, 1371, 1210, 1069, 878, 768, 692
cm–1.
1H NMR: d = 3.74 (s, 3 H, CH3), 7.54–7.57 (m, 3 H, Ph), 7.73–7.76
conditions, which enables to extend considerably the (m, 2 H, Ph), 8.57 (s, 1 H, CH).
13C NMR: d = 32.0, 127.1, 128.3, 128.8, 129.7, 146.1, 153.2.
range of usable 4,5-substituents.
MS–EI: m/z (Irel) = 159 (50) [M+], 158 (100), 104 (35), 89 (30), 77
(33).
MnO2 was purchased from Acros (precipitated active, 88%). 1H and
13C NMR spectra were measured on a Bruker Avance DRX 400
spectrometer (1H NMR: 400 MHz; 13C NMR: 100 MHz) in DMSO-
Anal. Calcd for C9H9N3 (159.19): C, 67.91; H, 5.70; N, 26.40.
Found: C, 68.00; H, 5.70; N, 26.27.
Synthesis 2006, No. 1, 156–160 © Thieme Stuttgart · New York

158
N. V. Ivanova et al.
PAPER
3,4-Diphenyl-4H-1,2,4-triazole (2d)4,15
Yield: 86%; beige crystals; mp 138–140 °C.
MS–EI: m/z (Irel) = 189 (100) [M+], 188 (50), 118 (35), 104 (70), 77
(65), 57 (75).
IR (KBr): 3160, 1690, 1592, 1503, 1462, 1385, 1210, 1068, 848,
767, 690 cm–1.
Anal. Calcd for C10H11N3O (189.22): C, 63.48; H, 5.86; N, 22.21.
Found: C, 63.41; H, 5.85; N, 22.31.
1H NMR: d = 7.38–7.39 (m, 7 H, Ph), 7.51–7.52 (m, 3 H, Ph), 8.86
4,5-Diphenyl-4H-1,2,4-triazol-3-yl)methanol (3d)
Yield: 81%; white crystals; mp 212–213 °C.
(s, 1 H, CH).
13C NMR: d = 126.1, 126.7, 128.4, 128.6, 129.3, 129.7, 129.8,
134.5, 145.6, 152.3.
MS–EI: m/z (Irel) = 221 (70) [M+], 220 (100), 91 (55), 77 (60), 51
(35).
IR (KBr): 3128, 2834, 1597, 1497, 1447, 1341, 1078, 1034, 1019,
800, 772, 690 cm–1.
1H NMR: d = 4.44 (d, J = 5.5 Hz, 2 H, CH2), 5.43 (t, J = 5.5 Hz, 1
H, OH), 7.33–7.42 (m, 7 H, Ph), 7.51–7.53 (m, 3 H, Ph).
13C NMR: d = 53.4, 127.1, 127.7, 128.2, 128.5, 129.5, 129.6, 129.7,
134.4, 153.6, 155.2.
MS–EI: m/z (Irel) = 251 (75) [M+], 250 (70), 118 (65), 104 (30), 91
Anal. Calcd for C14H11N3·0.2 M H2CO3 (233.67): C, 72.99; H, 4.92;
N, 17.98. Found: C, 73.11; H, 4.61; N, 17.73; compound actively
absorbs CO2 and water from air.
Hydroxymethylation of Triazoles; General Procedure
(55), 77 (100), 51 (50).
Method A: Paraformaldehyde (5 g, 0.167 mol) was added to a solu-
tion of the corresponding 2 (0.033 mol) in o-xylene (15 mL). The
reaction mixture was refluxed for 3 h at 125 °C (TLC on silica gel;
CHCl3–MeOH, 9:1). The reaction mixture was passed through a
layer of Celite, and the latter was washed with CHCl3 (3 × 15 mL).
The solvent was evaporated. The residue was purified by column
chromatography (silica gel, CHCl3–MeOH, 100:0 → 50:50).
Anal. Calcd for C15H13N3O (251.29): C, 71.70; H, 5.21; N, 16.72.
Found: C, 71.79; H, 5.23; N, 16.70.
2-[5-(Hydroxymethyl)-4-methyl-4H-1,2,4-triazol-3-yl]ethanol
(6)
Yield: 50%; white crystals; mp 117–118 °C.
IR (KBr): 3210, 2852, 1527, 1470, 1370, 1044, 976, 789, 739, 701
cm–1.
1H NMR: d = 2.84 (t, J = 6.6 Hz, 2 H, CH2), 3.56 (s, 3 H, CH3), 3.72
(td, J = 5.4, 6.7 Hz, 2 H), 4.55 (d, J = 5.6 Hz, 2 H, CH2), 4.83 (t,
J = 5.4 Hz, 1 H, OH), 5.46 (t, J = 5.6 Hz, 1 H, OH).
13C NMR: d = 28.0, 29.7, 53.8, 59.2, 153.5, 153.9.
MS–EI: m/z (Irel) = 157 (18) [M+], 156 (68), 140 (88), 138 (32), 127
(96), 126 (65), 98 (55), 91 (35), 73 (32), 72 (48), 61 (75), 57 (100),
56 (80), 55 (62).
Method B: For the synthesis of 3a, triazole 2a was heated in a 37%
aq solution of formaldehyde (0.33 mol) for 3 h at 90 °C. After evap-
oration to dryness, the residue was treated as described in method A.
(4,5-Dimethyl-4H-1,2,4-triazol-3-yl)methanol (3a)
Yield: 73%; white crystals; mp 163–164 °C.
IR (KBr): 3120, 2831, 1530, 1432, 1335, 1029, 973, 793, 710 cm–1.
1H NMR: d = 2.31 (s, 3 H, CH3), 3.53 (s, 3 H, CH3), 4.54 (d, J = 3.7
Hz, 2 H, CH2), 5.46 (br t, J = 3.7 Hz, 1 H, OH).
13C NMR: d = 10.1, 29.6, 53.7, 151.8, 153.9.
MS–EI: m/z (Irel) = 127 (95) [M+], 126 (70), 98 (45), 57 (70), 56
Anal. Calcd for C6H11N3O2 (157.17): C, 45.85; H, 7.05; N, 26.73.
Found: C, 45.51; H, 7.02; N, 26.05.
(100), 55 (45).
Reaction of 3a–d with SOCl2; General Procedure
Anal. Calcd for C5H9N3O (127.15): C, 47.23; H, 7.13; N, 33.05.
Found: C, 47.25; H, 7.16; N, 33.04.
A solution of pyridine (11.3 g, 0.143 mol) in CH2Cl2 (2 mL) was
added to a solution of the corresponding 3 (0.13 mol) in CH2Cl2 (50
mL). A solution of SOCl2 (20.1 g, 0.169 mol) in CH2Cl2 (2 mL) was
added to this mixture under stirring at 0 °C. The ice bath was then
removed, and the stirring was continued at r.t. for 3 h (TLC on silica
gel; CHCl3–MeOH, 9:1). A sat. aq solution of NaHCO3 (100 mL)
was added to the reaction mixture. The organic layer was separated,
and the aqueous one was washed with CH2Cl2 (2 × 100 mL). The
combined extracts were dried with Na2SO4 and evaporated. The res-
idue was purified by column chromatography on silica gel
(CH2Cl2–MeCN, 100:0 → 50:50).
5-Methyl-4-phenyl-4H-1,2,4-triazol-3-yl)methanol (3b)
Yield: 90%; white crystals; mp 212–213 °C.
IR (KBr): 3182, 3054, 1594, 1533, 1497, 1415, 1323, 1035, 806,
762, 690 cm–1.
1H NMR: d = 2.18 (s, 3 H, CH3), 4.36 (d, J = 4.9 Hz, 2 H, CH2), 5.30
(br t, J = 4.9 Hz, 1 H, OH), 7.45–7.47 (m, 2 H, Ph), 7.54–7.60 (m,
3 H, Ph).
13C NMR: d = 10.7, 53.4, 127.1, 129.3, 129.7, 133.9, 151.3, 153.9.
MS–EI: m/z (Irel) = 189 (65) [M+], 118 (100), 91 (95), 77 (90), 51
For the synthesis of compound 3a, the reaction was carried out with-
out addition of pyridine solution. When the reaction was completed,
the solvent was evaporated, and the residue was triturated with
Et2O.
(40).
Anal. Calcd for C10H11N3O (189.22): C, 63.48; H, 5.86; N, 22.21.
Found: C, 63.28; H, 5.84; N, 22.18.
3-(Chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole Hydrochlo-
ride (4a)
Yield: 96%; white crystals; mp 159–161 °C.
4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methanol (3c)
Yield: 96%; white crystals; mp 183–184 °C.
IR (KBr): 3003, 2947, 1518, 1483, 1435, 1360, 1275, 1149, 775,
738, 710, 657 cm–1.
1H NMR: d = 2.35 (s, 3 H, CH3), 3.56 (s, 3 H, CH3), 4.94 (s, 2 H,
CH2).
13C NMR: d = 10.2, 29.9, 34.6, 150.6, 152.9.
MS–EI: m/z (Irel) = 145 (45) [M+], 110 (100), 56 (90).
IR (KBr): 3095, 1521, 1489, 1464, 1323, 1054, 1031, 774, 700
cm–1.
1H NMR: d = 3.69 (s, 3 H, CH3), 4.66 (d, J = 5.6 Hz, 2 H, CH2), 5.57
(t, J = 5.6 Hz, 1 H, OH), 7.53–7.56 (m, 3 H, Ph), 7.68–7.70 (m, 2 H,
Ph).
13C NMR: d = 31.2, 53.9, 127.4, 128.5, 128.9, 129.8, 154.5, 155.1.
Anal. Calcd for C5H8ClN3·HCl (182.06): C, 32.99; H, 4.98; Cl,
38.95; N, 23.08. Found: C, 33.23; H, 4.95; Cl, 38.60; N, 23.20.
Synthesis 2006, No. 1, 156–160 © Thieme Stuttgart · New York

PAPER
Convenient Synthesis of 4,5-Disubstituted 1,2,4-Triazoles
IR (KBr): 1706, 1498, 1457, 1052, 821, 692 cm–1.
159
3-(Chloromethyl)-5-methyl-4-phenyl-4H-1,2,4-triazole (4b)
Yield: 75%; light-yellow crystals; mp 125–127 °C.
1H NMR: d = 2.27 (s, 3 H, CH3), 7.47–7.49 (m, 2 H, Ph), 7.56–7.58
IR (KBr): 1591, 1496, 1426, 1339, 1259, 797, 744, 699, 674, 544
cm–1.
1H NMR: d = 2.20 (s, 3 H, CH3), 4.71 (s, 2 H, CH2), 7.51–7.54 (m,
2 H, Ph), 7.59–7.65 (m, 3 H, Ph).
13C NMR: d = 10.7, 34.4, 127.2, 129.9, 130.0, 132.2, 150.6, 152.6.
MS–EI: m/z (Irel) = 207 (30) [M+], 173 (35), 172 (100), 131 (75), 91
(m, 3 H, Ph), 9.87 (s, 1 H, CHO).
13C NMR: d = 10.4, 126.8, 129.5, 129.7, 133.5, 151.1, 154.9, 180.7.
MS–EI: m/z (Irel) = 187 (80) [M+], 158 (35), 118 (100), 91 (75), 77
(85), 65 (40), 51 (58).
Anal. Calcd for C10H9N3O (187.20): C, 64.16; H, 4.85; N, 22.45.
Found: C, 64.11; H, 4.84; N, 22.24.
(40), 77 (75), 51 (55).
4-Methyl-5-phenyl-4H-1,2,4-triazole-3-carbaldehyde (5c)
Yield: 71%; white crystals; mp 116–118 °C.
IR (KBr): 1700, 1494, 1450, 1349, 1100, 805, 775, 728, 698 cm–1.
Anal. Calcd for C10H10ClN3 (207.66): C, 57.84; H, 4.85; Cl, 17.07;
N, 20.23. Found: C, 57.61; H, 4.96; Cl, 17.34; N, 20.18.
3-(Chloromethyl)-4-methyl-5-phenyl-4H-1,2,4-triazole (4c)
Yield: 88%; white crystals; mp 127–129 °C.
IR (KBr): 1493, 1458, 1396, 769, 741, 695, 667, 631, 540 cm–1.
1H NMR: d = 3.73 (s, 3 H, CH3), 5.07 (s, 2 H, CH2), 7.56–7.58 (m,
3 H, Ph), 7.72–7.74 (m, 2 H, Ph).
13C NMR: d = 31.5, 34.6, 127.0, 128.7, 128.9, 130.1, 151.9, 155.2.
MS–EI: m/z (Irel) = 207 (50) [M+], 173 (35), 172 (100), 118 (85),
1H NMR: d = 3.91 (s, 3 H, CH3), 7.61–7.63 (m, 3 H, Ph), 7.77–7.80
(m, 2 H, Ph), 10.06 (s, 1 H, CHO).
13C NMR: d = 32.8, 125.6, 129.0, 129.2, 130.8, 151.8, 156.9, 182.8.
MS–EI: m/z (Irel) = 187 (60) [M+], 158 (20), 104 (100), 103 (40), 77
(70), 76 (32), 55 (35), 51 (42).
Anal. Calcd for C10H9N3O (187.20): C, 64.16; H, 4.85; N, 22.45.
Found: C, 64.28; H, 4.83; N, 22.29.
104 (35), 103 (55), 77 (80), 76 (30), 51 (55).
4,5-Diphenyl-4H-1,2,4-triazole-3-carbaldehyde (5d)
Yield: 75%; white crystals; mp 166–168 °C.
IR (KBr): 1698, 1495, 1436, 1133, 818, 759, 687 cm–1.
Anal. Calcd for C10H10ClN3 (207.66): C, 57.84; H, 4.85; Cl, 17.07;
N, 20.23. Found: C, 57.70; H, 4.92; Cl, 17.10; N, 20.25.
3-(Chloromethyl)-4,5-diphenyl-4H-1,2,4-triazole (4d)
Yield: 96%; white crystals; mp 156–158 °C.
IR (KBr): 1592, 1492, 1470, 1440, 1251, 780, 695, 567 cm–1.
1H NMR: d = 4.78 (s, 2 H, CH2), 7.32–7.42 (m, 5 H, Ph), 7.47–7.51
(m, 2 H, Ph), 7.55–7.58 (m, 3 H, Ph).
13C NMR: d = 34.2, 126.6, 127.8, 128.2, 128.6, 129.9, 130.0, 130.1,
133.7, 151.9, 154.4.
1H NMR: d = 7.35–7.54 (m, 10 H, Ph), 9.95 (s, 1 H, CHO).
13C NMR: d = 125.6, 127.6, 128.7, 128.8, 129.5, 129.9, 130.6,
133.9, 151.6, 155.7, 180.9.
MS–EI: m/z (Irel) = 249 (80) [M+], 248 (65), 220 (20), 118 (70), 104
(30), 91 (88), 77 (100), 51 (80).
Anal. Calcd for C15H11N3O (249.27): C, 72.28; H, 4.45; N, 16.86.
Found: C, 72.09; H, 4.36; N, 16.79.
MS–EI: m/z (Irel) = 269 (35) [M+], 234 (90), 91 (30), 77 (100), 51
(65).
References
Anal. Calcd for C15H12ClN3 (269.74): C, 66.79; H, 4.48; Cl, 13.14;
N, 15.58. Found: C, 66.77; H, 4.48; Cl, 13.09; N, 15.39.
(1) (a) Kakefuda, A.; Suzuki, T.; Tobe, T.; Tahara, A.;
Sakamoto, S.; Tsukamoto, S. Bioorg. Med. Chem. 2002, 10,
1905. (b) Kurup, A.; Garg, R.; Carini, D. J.; Hansch, C.
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Oxidation of 3a–d to Aldehydes; General Procedure
MnO2 (10 g, 0.115 mol) was added to the corresponding 3 (0.011
mol) in absolute THF (50 mL). The reaction mixture was stirred at
r.t. for 2 h (TLC on silica gel; CHCl3–MeOH, 9:1). The reaction
mixture was passed through a layer of Celite, and the latter was
washed with CH2Cl2 (5 × 100 mL). The solvent was evaporated.
The residue was purified by column chromatography on silica gel
(CH2Cl2–MeCN 100:0 → 50:50).
4,5-Dimethyl-4H-1,2,4-triazole-3-carbaldehyde (5a)
Yield: 94%; white crystals; mp 89–90 °C.
(4) (a) Hoggarth, A. J. Chem. Soc. 1949, 1163. (b) Hoggarth,
A. J. Chem. Soc. 1950, 1579.
IR (KBr): 1687, 1511, 1454, 1355, 1068, 812 cm–1.
(5) (a) Hester, J. B.; VonVoigtlander, P.; Evenson, G. N. J. Med.
Chem. 1980, 23, 873. (b) Hester, J. B. J. Heterocycl. Chem.
1980, 17, 575. (c) Martin, A.; Diaz, J. A.; Vega, S. An.
Quim. 1995, 91, 3.
(6) Larsen, S. D.; DiPaolo, B. A. Org. Lett. 2001, 3, 3341.
(7) (a) Hester, J. B.; Rudzik, A. D.; VonVoigtlander, P. J. Med.
Chem. 1980, 23, 643. (b) Gall, M.; Kamdar, B. V.; Collins,
R. J. J. Med. Chem. 1978, 21, 1290.
(8) Robert-Piessard, S. C.; Leger, J. M.; Kumar, P.; Baut, G. L.;
Brion, J. D. J. Chem. Res., Miniprint 1989, 3, 511.
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1H NMR: d = 2.44 (s, 3 H, CH3), 3.78 (s, 3 H, CH3), 9.93 (s, 1 H,
CHO).
13C NMR: d = 9.8, 31.0, 151.2, 155.7, 182.5.
MS–EI: m/z (Irel) = 125 (80) [M+], 96 (40), 69 (45), 56 (100), 55
(80).
Anal. Calcd for C5H7N3O (125.13): C, 47.99; H, 5.64; N, 33.58.
Found: C, 47.89; H, 5.69; N, 33.46.
5-Methyl-4-phenyl-4H-1,2,4-triazole-3-carbaldehyde (5b)
Yield: 77%; white crystals; mp 180–181 °C.
(10) Young, O. J. Chem. Soc. 1901, 79, 668.
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N. V. Ivanova et al.
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