Monocyclic 1,2,3-triazin-4(3H)-ones: Synthesis, structure and photochemical behaviour

Article abstract of DOI:10.1002/ejoc.200600119

Oxidation of the easily available 1-(alkylamino)pyrazolones allows the preparation of the title compounds, which are a new class of heterocycles, in good yields. The structure of these compounds is assigned on the basis of HR mass spectroscopy and sodium

Full text of DOI:10.1002/ejoc.200600119

FULL PAPER
DOI: 10.1002/ejoc.200600119
Monocyclic 1,2,3-Triazin-4(3H)-ones: Synthesis, Structure and Photochemical
Behaviour
Angela Maria Celli,[a] Serena Ferrini,[a] and Fabio Ponticelli*[a]
Keywords: Nitrogen heterocycles / Oxidation / Photochemistry / Rearrangements
Oxidation of the easily available 1-(alkylamino)pyrazolones
allows the preparation of the title compounds, which are a
new class of heterocycles, in good yields. The structure of
these compounds is assigned on the basis of HR mass spec-
troscopy and sodium borohydride reduction to (Z,E)-2-
methyl-3-phenyl-N-(1-phenylethyl)acrylamide. Ring con-
traction/rearrangement to 2-alkyl-2H-1,2,3-triazole is ob-
served under UV irradiation. A possible mechanistic rational-
isation of the observed processes is proposed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
However, when aminopyrazolones 1a,b were treated with
copper acetate in methanol, an unexpected ring fragmenta-
tion/solvent addition occurred to give the enamino esters
2a,b (Scheme 1).
Introduction
Ring-condensed 1,2,3-triazin-4-ones are a class of het-
erocyclic derivatives that have been widely investigated for
their biological and chemical properties, and compounds
with sedative, diuretic, anaesthetic, antiarthritic and antitu-
moural activities have been reported.[1] Suitably substituted
benzo-1,2,3-triazin-4-ones have been described as potent in-
hibitors of matrix metalloproteinases,[2] recombinant hu-
man histone deacetylases[3] and as ligands of 5-HT1A sero-
tonin receptors.[4] In addition, they are used as an activating
moiety in coupling agents for the preparation of peptides
and modified nucleosides.[5] However, in spite of a potential
analogous interest, the corresponding monocyclic deriva-
tives are completely unknown: to the best of our knowl-
edge, only the preparation of some mesoionic compounds
belonging to the 1,2,3-triazin-4,6-dione has been re-
ported.[6]
On the other hand, treatment of the N-(alkylamino)pyraz-
olones 1c,d with the same reagent gave the 1,2,3-triazinones
3c,d in good yields. A slower but identical reaction was ob-
served when 1c,d was treated with oxygen in the presence of
a mild base such as sodium hydrogen carbonate. It should be
noted that the corresponding imine 4c, which is a potential
intermediate for the transformation of 1c into 3c, is com-
pletely unaltered under the above reaction conditions.
A possible rationalisation of the oxidative behaviour of
differently substituted 1-aminopyrazolones is reported in
Scheme 2. Ring enlargement/oxidation of the starting mate-
rial affords, when R is not H, a stable and isolable 3-alkyl-
1,2,3-triazin-4(3H)-one (compounds 3c,d). Otherwise, when
R = RЈ = H or R = H and RЈ = Me, an unstable 1,2,3-
triazin-4(1H)-one is formed, which, after solvent attack on
the activated carbonyl group followed by N2 loss, finally
gives the enamino esters 2a,b.
In this paper we describe a facile access to the title com-
pounds and some aspects of their reactivity, with the pur-
pose of structural assignment and gaining information
about heterocyclic ring photochemical behaviour.
As far as the structure of the new compounds 3c,d is
concerned, the presence of the 1,2,3-triazin-4-one system
was supported by analytical and spectroscopic data (see
Exp. Sect.). In particular, the N=N–N–R sequence was de-
duced by mass spectroscopy, which shows the loss of 28
amu from the molecular ion: HRMS analysis allowed us to
assign this process to the elimination of a molecule of N2.
Furthermore, the substituent positions on the 1,2,3-triazin-
one system followed from the reductive transformation of
3c into a mixture of the (E,Z)-amides 5 and 6 (Scheme 3).
To confirm this assignment, compound 5 was indepen-
dently prepared by treatment of (E)-2-methyl-3-phenyl-
acryloyl chloride with 1-phenylethylamine; photochemical
isomerisation of compound 5 also allowed us to obtain the
(Z)-isomer 6.
Results and Discussion
Benzo-fused 1,2,3-triazine derivatives and several mono-
cyclic aromatic 1,2,3-triazines are usually prepared by oxi-
dative rearrangement of a suitably substituted N-aminopyr-
azole.[7] As a consequence, we decided to extend this strat-
egy to the synthesis of monocyclic 1,2,3-triazin-4-ones by
using aminopyrazolones, a class of heterocyclic derivatives
which some years ago we considered from a synthetic and
chemical reactivity point of view, as substrates.[8]
[a] Dipartimento di Chimica, Università di Siena,
Via A. Moro 2, 53100 Siena, Italy
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A. M. Celli, S. Ferrini, F. Ponticelli
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Scheme 1.
Scheme 2.
Scheme 3.
spectrum of this compound and lack of an NOE to the
phenyl protons of the N-substituent upon irradiation of the
methyl signal at δ = 2.47 ppm suggests the unexpected pho-
tochemical formation of compound 7, as shown in
Scheme 4.
Scheme 4.
In order to confirm this structural assignment, we de-
cided to independently prepare all the N-(1-phenylethyl)-
phenylmethyl-substituted 1,2,3-triazoles. As shown in
Scheme 5, compounds 8 and 9 were obtained by reaction
of (1-azidoethyl)benzene with methyl benzyl ketone or pro-
piophenone, respectively, following a procedure previously
reported for the selective access to 1-substituted triazoles.[10]
Compound 7 was prepared as the main product by alky-
lation of the corresponding 4-methyl-5-phenyl-1,2,3-triazole
Following our continuing interest in the synthetic and with 1-chloro-1-phenylethane in the presence of a base.
mechanistic aspects of heterocycles’ photochemistry,[9] and Minor amounts of the isomers 8 and 9 were also obtained.
owing to the novelty of this class of 1,2,3-triazinone deriva- In this way it was possible to unequivocally assign the struc-
tives, we also studied their photoreactivity with the aim of ture 7 to the photochemical product obtained from 3c. It
investigating the potential synthetic value of this process. should be noted that the triazoles 8 and 9 are stable under
UV irradiation gave a slow transformation of the triazinone the same irradiation conditions. As a consequence, the pho-
3c into a product of molecular formula C17H17N3, deriving tochemical path from 3c to 7 requires, after CO elimination,
from the loss of a CO moiety, which can be presumably a molecular rearrangement of the heterocyclic system. A
identified as an N-substituted 1,2,3-triazole derivative. Ab- possible mechanistic scheme for the formation of 7 is shown
sence of an [M – 28] ([M – N2]) fragment in the HR mass in Scheme 4. In analogy with the well known oxa-di-π-
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Monocyclic 1,2,3-Triazin-4(3H)-ones
FULL PAPER
residue was chromatographed with chloroform to give compound
methane photorearrangement of substituted 2,4-cyclohexa-
dienones[11a,b] and of the very similar behaviour of the cor-
responding aza-analogue pyridones,[11c] the excited 1,2,3-
triazin-4(3H)-one system affords an unstable 1,5,6-triazabi-
cyclo[3.1.0]hex-3-en-2-one, which finally gives the stable,
aromatic triazole 7 by loss of carbon monoxide.
1c (0.35 g, 87% yield), which was crystallised from cyclohexane,
1
m.p. 127–128 °C. H NMR:[13] δ = 1.14* (d, J = 8.0 Hz, 1.7 H, 4-
Me), 1.39, 1.45*,# (d, J = 8.0 Hz, 3 H, 2-CHMe), 2.01# (s, 1.3 H,
4-Me), 3.42* (q, J = 8.0 Hz, 0.6 H, 4-CH), 4.12 (m, 1.4 H, NH/
OH), 4.63 (m, 1 H, 2-CHMe), 7.35–7.61 (m, 10 H, aryl) ppm. ESI
MS: m/z (%) 609 (54) [2M+Na]+, 316 (100) [M+Na]+, 294 (14)
[MH]+. C18H19N3O (293.15): calcd. C 73.72, H 6.48, N 14.33;
found C 73.90, H 6.75, N 14.10.
2-(Benzhydrylamino)-4-methyl-5-phenyl-1,2-dihydropyrazol-3-one
(1d): A mixture of benzophenone (1.45 g, 8.0 mmol) and 1a (1 g,
5.3 mmol) was heated at 90 °C for 3 h. After cooling to room temp.,
the reaction mixture was sublimed at 100 °C and 0.5 Torr for ap-
proximately 2 h to remove the excess benzophenone. The solid resi-
due was washed with diethyl ether and filtered to give 2-(diphenyl-
methyleneamino)-4-methyl-5-phenyl-1,2-dihydropyrazol-3-one (4d;
1.08 g, 58% yield), which was recrystallised from ligroin, m.p. 178–
181 °C. 1H NMR:[13] δ = 1.41* (d, J = 8.0 Hz, 1.8 H, 4-CHMe),
2.07# (s, 1.2 H, 4-Me), 3.50# (q, J = 7.8 Hz, 0.6 H, 4-CH), 7.33–
7.80 (m, 15 H, aryl) ppm. C23H19N3O (353.15): calcd. C 78.16, H
5.42, N 11.89; found C 78.01, H 5.58, N 11.63.Catalytic hydrogena-
tion of 4d, as described above for the synthesis of 1c, gave com-
1
pound 1d (65% yield), m.p. 67–70 °C from benzene. H NMR:[13]
Scheme 5.
δ = 1.15* (d, J = 7.8 Hz, 1.8 H, Me), 1.97# (s, 1.2 H, 4-Me), 4.92
(m, 1.4 H, NH/OH), 3.37* (q, J = 7.8 Hz, 0.6 H, 4-CH), 5.20# (s,
0.4 H, 2-CHPh), 5.76* (s, 0.6 H, 2-CHPh), 7.02–8.20 (m, 15 H,
aryl) ppm. ESI MS: m/z (%) 733 (23) [2M+Na]+, 378 (30)
[M+Na]+, 356 (19) [MH]+. C23H21N3O (355.17): calcd. C 77.72,
H 5.96, N 11.82; found C 77.65, H 5.56, N 12.10.
Conclusions
Oxidation of N-(alkylamino)pyrazolones is a good and
general strategy for the preparation of monocyclic 1,2,3-
triazin-4-ones. The photochemical behaviour of these com-
pounds (loss of carbon monoxide and rearrangement to a
2-alkyl-2H-1,2,3-triazole) is completely different from
benzo-condensed 1,2,3-triazinones, for which N2 elimi-
nation and benzoazetidinone formation was previously ob-
served.[12]
General Procedure for the Oxidation of Compounds 1a–d: Anhy-
drous copper acetate (3.5 mmol) was added to a solution of com-
pounds 1a–d (3.5 mmol) in methanol (75 mL) and the mixture
stirred at reflux until the starting material disappeared (TLC). Af-
ter filtration of the insoluble inorganic solid, the solvent was re-
moved in vacuo and the residue column chromatographed with
chloroform to give compounds 2a,b or 3c,d, respectively.
Methyl 3-Amino-2-methyl-3-phenylacrylate (2a): The residue ob-
tained from compound 1a was identified as the aminoacrylate 2a
(0.52 g, 78% yield) by comparison with an authentic sample.[14]
Experimental Section
General: Melting points were determined on a Kofler hot stage
Methyl 2-Methyl-3-(methylamino)-3-phenylacrylate (2b): The resi-
due obtained from compound 1b was identified as the methylami-
nolacrylate 2b (0.54 g, 75% yield) by comparison with an authentic
sample.[15]
1
and are uncorrected. H and 13C NMR spectra were recorded for
solutions in CDCl3 on a Bruker AC 200 spectrometer at 200.13
and 50.33 MHz, respectively. Chemical shifts are reported in ppm
from internal TMS. All chemicals were of reagent grade and were
used without purification. Photochemical reactions were carried
out in a quartz apparatus with a low-pressure mercury immersion
lamp (12 W); nitrogen was bubbled constantly through the irradi-
ated solution. The EI and FAB mass spectra were recorded with a
VG 70 250S instrument in low resolution mode (1000 M/∆M, 10%
valley) or high resolution mode (EI-HRMS, 10,000 M/∆M, 10%
valley); electrospray ionisation spectra (ESI MS) were recorded
with a LCQ-DECA Thermo Finnigan instrument. Analytical or
preparative chromatography was performed on precoated 4×6.7 or
20×20 silica gel 60 F254 plates, respectively. Column chromatog-
raphy was carried out on silica gel (0.063–0.2 mm). Compounds
1a,b were prepared as described previously.[8c]
5-Methyl-6-phenyl-3-(1-phenylethyl)-1,2,3-triazin-4(3H)-one
(3c):
The residue obtained from compound 1c was purified by sublima-
tion in vacuo to give the 1,2,3-triazinone 3c as white needles
(0.77 g, 75.6% yield), m.p. 88–90 °C. 1H NMR: δ = 1.99 (d, J =
7.8 Hz, 3 H, 3-CHMe), 2.22 (s, 3 H, 5-Me), 6.37 (q, J = 7.8 Hz, 1
H, 3-CHMe), 7.32–7.55 (m, 10 H, aryl) ppm. 13C NMR: δ = 12.34,
20.11, 57.03, 125.15, 127.49, 128.07, 128.35, 128.56, 129.20, 129.62,
134.45, 139.82, 153.96, 157.34 ppm. FAB MS: m/z (%) 292 (100)
[MH]+, 264 (32), 220 (8), 188 (63), 160 (32), 105 (94). EI HRMS:
m/z (%) 291.1371 (0.5) [M]+, 263.1427 (26) [M – N2]+. C18H17N3O
(291.14): calcd. C 74.20, H 5.88, N 14.42; found C 73.90, H 5.60,
N 14.71.
4-Methyl-5-phenyl-2-(1-phenylethylamino)-1,2-dihydropyrazol-3-one
(1c): 5% Pd/C (0.125 g) was added to a solution of 4-methyl-5-
phenyl-2-(1-phenylethylideneamino)-1,2-dihydropyrazol-3-one[8a]
(0.40 g, 1.37 mmol) in methanol (20 mL) and the mixture was hy-
drogenated (room temp.) overnight at 30 psi. After removal of the
catalyst by filtration, the solution was evaporated in vacuo and the
3-Benzhydryl-5-methyl-6-phenyl-1,2,3-triazin-4(3H)-one (3d): The
residue obtained from compound 1d was purified by crystallisation
from light petroleum to give compound 3d as a white powder
(0.75 g, 60.4% yield), m.p. 127–129 °C. 1H NMR: δ = 2.29 (s, 3 H,
5-Me), 7.36–7.63 (m, 11 H, aryl and 3-CH) ppm. 13C NMR: δ =
13.52, 61.11, 121.61, 123.30, 123.79, 124.22, 124.60, 124.93, 125.26,
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A. M. Celli, S. Ferrini, F. Ponticelli
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125.71, 126.13, 126.59, 127.33, 130.75, 134.63, 150.28, 154.10 ppm.
(0.27 mL, 2 mmol). were added to a 1  solution of potassium tert-
butoxide in THF (2 mL). The reaction mixture turned red immedi-
ESI MS: m/z (%) 729 [2M+Na]+, 392 [M+K]+, 376 [M+Na]+.
EI HRMS: m/z (%) 353.1526 (0.7) [M]+, 325.1467 (23) [M – N2]+. ately and was stirred at room temperature for 2 h. It was then
C23H19N3O (353.15): calcd. C 78.17, H 5.42, N 11.89; found C
78.26, H 5.49, N 11.82.
poured into ice/water to give an oil, which was extracted with di-
ethyl ether. The ethereal solution was dried over anhydrous magne-
sium sulfate and then evaporated to give compound 8 (0.15 g, 32%
yield; m.p. 103–105 °C) after crystallisation from ethyl acetate/light
petroleum. 1H NMR: δ = 2.07 (d, J = 7.1 Hz, 3 H, 1-CHMe), 2.25
(s, 3 H, 5-Me), 5.57 (q, 1 = H, J = 7.1 Hz, 1-CH), 7.18–7.45, 7.65–
7.68 (m, 10 H, aryl) ppm. 13C NMR: δ = 9.11, 21.82, 58.66, 125.95,
127.17, 127.45, 127.94, 128.49, 128.86, 128.94, 131.61, 140.62,
144.86 ppm. EI MS: m/z (%) 263 (25) [M]+, 235 (3), 220 (9).
C17H17N3 (263.14): calcd. C 77.54, H 6.51, N 15.96; found C 77.63,
H 6.65, N 16.03.
(E)-2-Methyl-3-phenyl-N-(1-phenylethyl)acrylamide (5): A solution
of 1-phenylethylamine (0.4 g, 2 mmol) in diethyl ether (25 mL) was
slowly added to a solution of (E)-2-methyl-3-phenylacryloyl chlo-
ride (0.3 g) in diethyl ether (10 mL). After 1 h the mixture was
washed with 0.1  HCl solution and then with water. The ethereal
solution was separated, dried with Na2SO4 and evaporated to af-
ford the (E)-amide 5 (0.35 g, 80%), which was crystallised from
1
ethanol/water. M.p. 96–97 °C. H NMR: δ = 1.60 (d, J = 6.9 Hz,
3 H, NHCHMe), 2.12 (d, J = 1.4 Hz, 3 H, 2-Me), 5.28 (quint, J =
6.9, 1 H, NHCHMe), 6.27 (d, J = 6.9 Hz, 1 H, NH), 7.26–7.50 (m,
11 H, aryl and 3-CH) ppm. C18H19NO (265.15): calcd. C 81.47, H
7.22, N 5.28; found C 81.62, H 7.05, N 5.11.
4-Methyl-5-phenyl-1-(1-phenylethyl)-1H-1,2,3-triazole (9): Op-
erating as above, a red solution was obtained from a 1  solution of
potassium tert-butoxide in THF (2 mL), (1-azidoethyl)benzene[17]
(0.27 mL, 2 mmol) and propiophenone (0.27 mL, 2 mmol), and
heated at 65 °C for 1 h in a closed tube. Water was then added to
the ice-cooled reaction mixture and this was extracted with diethyl
ether. The extracts were dried over anhydrous magnesium sulfate
and then evaporated to give the triazole 9 (0.30 g, 74% yield) as an
oil, which was purified by distillation at 60 °C and 0.05 Torr. 1H
NMR: δ = 1.95 (d, J = 3.0 Hz, 3 H, 1-CHMe), 2.24 (s, 3 H, 4-Me),
5.41 (q, J = 3.0 Hz, 1 H, 1-CH), 7.03–7.13, 7.21–7.26, 7.36–7.41
(m, 10 H, aryl) ppm. 13C NMR: δ = 10.47, 22.39, 58.44, 126.20,
127.75, 128.63, 128.75, 128.95, 129.73, 132.94, 133.66, 134.38,
141.26, 141.39 ppm. EI MS: m/z (%) 263 (24) [M]+, 248 (5), 235
(13). C17H17N3 (263.14): calcd. C 77.54, H 6.51, N 15.96; found C
77.68, H 6.42, N 15.75.
(Z)-2-Methyl-3-phenyl-N-(1-phenylethyl)acrylamide (6): A solution
of the amide 5 (0.1 g) in acetonitrile (100 mL) was irradiated, at
254 nm, with a low-pressure mercury lamp for 2.5 h. TLC and the
NMR spectrum of the reaction mixture indicated the formation of
a photostationary 1:1 mixture of (E) and (Z) isomers. The two
products were separated by preparative layer chromatography, elut-
ing with cyclohexane/ethyl acetate (2:1) to give (in order of elution)
the unreacted amide 5 (0.04 g) and the isomeric amide 6 (0.040 g)
as an oil. 1H NMR: δ = 1.30 (d, J = 7.0 Hz, 3 H, NHCHMe), 2.10
(d, J = 1.6 Hz, 3 H, 2-Me), 5.10 (quint, J = 7.0 Hz, 1 H,
NHCHMe), 5.45 (d, J = 7.0 Hz, 1 H, NH), 7.31–7.50 (m, 11 H,
aryl and 3-CH) ppm. C18H19NO (265.15): calcd. C 81.47, H 7.22,
N 5.28; found C 81.25, H 7.13, N 5.42.
(E,Z)-2-Methyl-3-phenyl-N-(1-phenylethyl)acrylamide (5 and 6): So-
dium borohydride (0.065 g, 1.7 mmol) was added to a solution of
the triazinone 3c (0.05 g, 0.17 mmol) in ethanol (15 mL). The mix-
ture was heated for 5 h at 80 °C in an ultrasound bath and then
evaporated, washed with acid water (10 mL), extracted with diethyl
ether and dried over Na2SO4. The ethereal solution was evaporated
to give a mixture of the two isomeric amides 5 and 6 in a 4:1 ratio,
as determined by NMR spectroscopy.
Acknowledgments
Permission to use the mass spectrometers in the “Centro di Analisi
e Determinazioni strutturali” of the University of Siena is grate-
fully acknowledged. This work supported by the University of Si-
ena, “Quota Servizi 2003/2004”.
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pound 7 (0.015 g, 42% yield, based on the unreacted starting mate-
1
rial). M.p. 127–128 °C. H NMR: δ = 1.99 (d, J = 7.2 Hz, 3 H, 2-
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CHMe), 2.47 (s, 3 H, 4-Me), 5.79 (q, J = 7.2 Hz, 1 H, 2-CH), 7.27–
7.47, 7.67–7.72 (m, 10 H, aryl) ppm. 13C NMR: δ = 11.78, 21.23,
64.11, 126.67, 127.20, 128.05, 128.14, 129.00, 131.58, 140.70,
141.24, 144.60 ppm. EI MS: m/z (%) 263 (100) [M]+, 248 (17). EI
HRMS: m/z (%) 263.1422 (32) [M]+, 248.1189 (12) [M – Me]+.
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80% yield) was obtained by refluxing 4-methyl-5-phenyl-1,2,3-tri-
azole[16] (1 g, 6.2 mmol) with 1-bromo-1-phenylethane (0.85 mL,
6.2 mmol) in anhydrous ethanol (10 mL) containing sodium
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doethyl)benzene[17] (0.27 mL, 1.8 mmol) and methyl benzyl ketone
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Monocyclic 1,2,3-Triazin-4(3H)-ones
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Received: February 10, 2006
Published Online: May 3, 2006
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