Direction of isomerization of 5-hydroxy-3-propargylthio-1,2,4-triazines according to 1H/15N heteronuclear multiple bond correlation (HMBC) spectra

Article abstract of DOI:10.1007/s10593-006-0100-8

We have studied isomerization of 6-substituted 5-hydroxy-3-propargylthio-1, 2,4-triazines using base catalysis. We have used NMR correlation spectroscopy (¹H/¹⁵N HMBC spectra) to prove the structure of the regioisomer formed. The typ

Full text of DOI:10.1007/s10593-006-0100-8

Chemistry of Heterocyclic Compounds, Vol. 42, No. 3, 2006
DIRECTION OF ISOMERIZATION OF 5-HYDROXY-
3-PROPARGYLTHIO-1,2,4-TRIAZINES ACCORDING
TO 1H/15N HETERONUCLEAR MULTIPLE BOND
CORRELATION (HMBC) SPECTRA
V. Yu. Smutin, V. A. Gindin, and N. O. Sablina
We have studied isomerization of 6-substituted 5-hydroxy-3-propargylthio-1,2,4-triazines using base
catalysis. We have used NMR correlation spectroscopy (1H/15N HMBC spectra) to prove the structure of
the regioisomer formed. The type of regioisomer formed (3,6-dimethylthiazolo[3,2-b]-1,2,4-triazin-7-
one) allows us to say that isomerization occurs as a direct propynyl rearrangement.
Keywords: 5-hydroxy-3-propargyl-1,2,4-triazine, 3-methyl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones,
rearrangement, regioisomer, 1H/15N HMBC spectra.
The process of isomerization of aromatic and heterocyclic propargyl ethers and thioethers, in particular
the Claisen and Cope rearrangements, has been vigorously studied to date. These processes are of significant
preparative importance for obtaining six-membered and five-membered condensed heterocycles. The results of
such studies are covered in monographs and reviews [1, 2]. Isomerization of heterocyclic thiopropargyl ethers,
especially ones containing several centers at which ring closure is possible, has been studied in significantly less
detail than for aromatic ethers. Substituted 5-hydroxy-3-propargylthio-1,2,4-triazines are specifically included
among such compounds. The first attempt to discuss the regiochemistry of the process of isomerization of
6-methyl-3-propargyl-1,2,4-triazin-5(2H)-one (1a) was made in [3]. The authors tried to determine whether a
[3,3]-sigmatropic rearrangement or direct nucleophilic addition of the amide functional group to the acetylene
moiety occurred. The reaction was carried out both in aprotic and in protic solvents at their boiling point and in
the presence of a Pd(II) complex as the catalyst. According to the results of the study in [3], in the presence of
Pd(PhCN)2Cl2, a mixture of products 2-4 is formed. Compound 3, as the authors noted, may also be the only
product if cyclization is catalyzed by NaOH.
CH2
Me
O
N
N
Me
O
N
N
Me
O
N
Me
O
N
N
NH
N
NH
+
+
S
S
N
S
N
H
S
3
C
HC
4
H2C
1
2
__________________________________________________________________________________________
Scientific-Research Institute of Chemistry, St. Petersburg State University, Petrodvorets, St. Petersburg
198504, Russia; e-mail: NMR@paloma.spbu.ru, rdch@sab.usr.pu.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 3, pp. 453-457, March, 2006. Original article submitted April 1, 2003.
0009-3122/06/4203-0403©2006 Springer Science+Business Media, Inc.
403

We should note that the authors of [3] isolated the intermediate products 2 and 3, i.e., the reaction does
not reach the step of aromatization of the methylidenethiazoline moiety. This is ensured by using solvents with
moderate basicity and a sufficiently long reaction time. To a significant extent, such reaction conditions are
probably the reason for the problem of structural identification of the isomers formed. Such identification is
1
based on the H NMR spectra: for compound 2, the chemical shifts of the protons of the exo-methylene moiety
differ by about 1.4 ppm. For its isomer 3, the chemical shifts of these signals are not very distinguishable.
In a study of different 6-substituted 5-hydroxy-3-propargylthio-1,2,4-triazines 1a-c, we also observed
that the reaction products have a bicyclic structure, and isomerization in aqueous base occurs practically
instantaneously in quantitative yield even at room temperature. With the aim of studying the step-by-step
formation of the bicyclic product, we obtained a model compound: propargylthio-1,2,4-triazine 1a, and studied
the process of its cyclization.
Theoretically possible isomerization routes for this compound are shown in the scheme below.
O
R
N
N
S
N
Me
5a–c
O
OH
N
O
Me
R3
R
R
N
N
N
N
N
N
S
N
H
S
S
N
6
C
CH
C
CH
1a–c
OH
O
N
R
R
N
N
N
N
N
S
S
O
C
R
N
CH2
Me
C
CH2
7
N
N
SH
O
R
N
N
N
S
Me
8
a R = Me, b R = Ph, c R = 2- H2NC6H4
Here we do not consider formation of the product with a thiazine ring rather than a thiazole ring, since
1
analysis of the H and 13C NMR spectra allows us to confidently say that closure of a five-membered ring
occurs: in the 1H NMR spectrum, the signal at 7.04 ppm corresponds to the aromatic proton of the thiazole ring,
and in the 13C NMR spectrum the signals at 103 ppm and 135 ppm correspond to the carbon atoms of the
thiazole ring. The structures of compounds 5-8, which are regioisomers, differ in the position of both the methyl
group and the proton of the thiazole ring relative to each of the nitrogen atoms of the triazine ring. Once we have
determined which regioisomer is formed, we can establish not only the direction of cyclization (at N(2) or
404

N(4) of the triazine ring), but also the nature of the isomerization: according to a Claisen type rearrangement, or
as a direct propynyl rearrangement.
1
We know [4, 5] that H/15N HMBC spectra have been successfully used to solve such problems.
Depending on the delay time τmb selected in the HMBC pulse sequence, in such a spectrum we can observe
correlations between nuclear spins through the number of bonds of interest. In the case under consideration, we
3
4
are interested in the spin–spin coupling constants through three and four bonds: J(N,H), J(N,H). According to the
3
4
data in [6, 7], in substituted six-membered nitrogen-containing heterocycles, J(N,H) = ~3 Hz while J(N,H) is
1
~1 Hz. Thus it is advisable to select the delay time in the H/15N HMBC experiment corresponding to this
1
interval of spin–spin coupling constants. The scheme below shows the three-bond and four-bond H/15N
correlations for 3,6-dimethyl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one.
8
7
O
8
N
9
N
O
S 1
6
S
2
4
N
Me
N
H
N
Me
5
4
N
3
5
Me
Me
The 1H/15N HMBC correlation spectra are shown in Fig. 1. In these spectra, we can observe cross peaks
arising due to interaction between the aromatic protons of the thiazole ring and N(5) (7.04 for F1 and -64 ppm
for F2), N(8) (7.04 for F1 and -146 ppm for F2) and N(4) (7.04 for F1 and -170 ppm for F2) and cross peaks
from interaction between protons of the methyl groups at the atoms C(6) and N(5) (2.27 for F1 and -60 ppm for
F2), and also at C(3) and N(4) (2.37 for F1 and -170 ppm for F2).
1
Thus the correlations observable in the H/15N HMBC spectrum of 3,6-dimethyl-7H-thiazolo[3,2-b]-
1,2,4-triazin-7-one for protons of the methyl groups allow us to pick out two possible structures (5 and 6) among
the four possible structures. For the aromatic proton of the thiazole ring, we observe three correlation peaks in
the spectrum; since the spectrum recording conditions allow us to observe correlations only through three and
four bonds, we can unambiguously give preference to structure 5.
EXPERIMENTAL
1
The H and 13C NMR spectra were taken on a Bruker DPX-300 spectrometer (300 MHz and 75 MHz
respectively) in DMSO-d6. The chemical shifts were measured relative to the residual solvent signal (in the
1
1H spectrum, at 2.50 ppm; in the 13C spectrum, at 39.6 ppm). Correlations of the H and 15N chemical shifts
through long-range spin–spin coupling constants were obtained by the HMBC method on a Bruker AMX-500
1
1
TABLE 1. H/15N Correlations Found in the H/15N HMBC Spectrum of
3,6-Dimethyl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one (5a)
NMR spectrum, δ, ppm
15N
1H
Reaction route
N(5)
-60
N(8)
N(4)
-170
-170
6-CH3
2.27
3-CH3
2-CH3
7.04
-140
N5↔H2, N8↔H2,
N4↔H2
N4↔C3-CH3
2.36
-60
N5↔C6-CH3
405

ppm
-190
-170
-150
-130
-110
-90
-70
-50
ppm
ppm
-200
-160
-120
-80
-40
ppm
Fig. 1. 1H/15N HMBC spectrum of 3,6-dimethyl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one.
spectrometer (500 MHz for 1H and 50 MHz for 15N respectively) using a 5-mm inverse detection probe (4 wt.%
solution in DMSO-d6 at room temperature). To improve the sensitivity and eliminate artifacts connected with
phase cycling, we used a modified HMBC pulse program using gs-HMBC pulsed field gradients [8-10] (invietgs
in the Bruker program library). The holding time (d4 in this program) was taken as equal to 0.109 sec, which
406

corresponds to the proposed spin–spin coupling constant J = 2.3 Hz. A sufficient signal-to-noise ratio was
1
achieved for 16 repetitions in each of the 68 experiments. The spectral ranges were 3822 Hz for H and
19212 Hz for 15N. In the 15N spectrum, the chemical shifts were measured relative to liquid NH3 (0 ppm at
25°C).
3,6-Dimethyl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one (5a). Triazine 1a (1 g, 5.5 mmol) was dissolved at
room temperature in a 9% aqueous solution of NaOH (15 ml). By 1 min later, a white precipitate began to form;
the reaction mixture was allowed to stand for 2-3 h, after which the precipitate was filtered out, washed with
water, and recrystallized from ethanol. Yield 0.7 g (70%). 1H NMR spectrum, δ, ppm (J, Hz): 2.28 (3H, s, CH3);
2.37 (3H, d, 4J = 1, CH3); 7.04 (1H, q, 4J = 1, H-2). 13C NMR spectrum, δ, ppm: 13.0 (CH3); 18.2 (CH3); 103.9
(C-2); 135.2 (C-3); 152.9 (C-6); 159.4 (C-7); 164.8 (C-9).
3-Methyl-6-phenyl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one (5b) was obtained analogously starting
1
from 5-hydroxy-6-phenyl-3-propargylthio-1,2,4-triazine. Yield 75%. H NMR spectrum, δ, ppm: 2.5 (3H, s,
CH3); 7.05 (1H, s, H-2); 7.5 (3H, m, Ar); 8.2 (2H, m, Ar). 13C NMR spectrum, δ, ppm: 12.5 (CH3); 104.1 (C-2);
127.6, 128.9, 130.2, 132.2, 134.5 (C-3); 147.8 (C-6); 157.3 (C-7); 163.2 (C-9).
6-(2'-Aminophenyl)-3-methyl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one
(5c).
A
solution
of
6-(2'-aminophenyl)-5-hydroxy-1,2,4-triazine-3-thiol (1 g, 4.5 mmol) in 9% aqueous KOH (10 ml) was stirred
with propargyl chloride (0.35 g, 4.7 mmol) for 3 h at ~20°C. The precipitate formed was separated after 12 h and
1
recrystallized from ethanol. Yield 0.8 g (69%). H NMR spectrum, δ, ppm: 2.4 (3H, s, CH3); 5.4 (2H, s, NH2);
6.6 (1H, t, J = 7.6, J = 8.1); 6.75 (1H, d, J = 9.1); 7.05 (1H, s, H-2); 7.15 (1H, t, J = 7.4, J = 7.6); 7.5 (1H, d, J =
8.5). 13C NMR spectrum, δ, ppm: 13.7 (CH3); 104.7 (C-2); 116.2, 117.1, 117.2, 131.4, 131.9, 135.8 (C-3); 148.7
(C-6); 151.7, 158.7 (C-7); 164.0 (C-9).
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