New methods for the selective alkylation of 3-thioxo-1,2,4-triazin-5-ones

Article abstract of DOI:10.1016/j.tetlet.2016.03.065

A method for regioselective alkylation of the 3-thiono-1,2,4-triazinone 10 at the sulfur atom is reported. Subsequent Claisen rearrangements, triggered either thermally or using a palladium catalyst, deliver N-alkylated products 13, while acid-catalysed r

Full text of DOI:10.1016/j.tetlet.2016.03.065

Tetrahedron Letters 57 (2016) 2215–2218
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New methods for the selective alkylation of 3-thioxo-1,2,4-triazin-5-
ones
Amany M. Ghanim a,b, David W. Knight a, , Nermine A. Osman , Hanan A. Abdel-Fattah , Azza M. Kadry
⇑
b
b
b
a
School of Chemistry, Cardiff University, Main College, Park Place, Cardiff CF10 3AT, UK
b
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazige University, Zagazig 44519, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for regioselective alkylation of the 3-thiono-1,2,4-triazinone 10 at the sulfur atom is reported.
Subsequent Claisen rearrangements, triggered either thermally or using a palladium catalyst, deliver N-
alkylated products 13, while acid-catalysed rearrangements of examples where a tertiary carbenium ion
can be generated, result in the formation of N-thioalkyl derivatives.
Received 11 February 2016
Revised 15 March 2016
Accepted 21 March 2016
Available online 7 April 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
3
-Thionyl-1,2,4-triazin-5-ones
S-alkylation
Claisen
Rearrangement
Acid-catalysed
The 1,2,4-triazine nucleus is well represented in the pharma-
ceived advantages of using this type of starting material were the
1
7
ceutical sector, in particular as a core component of a diversity of
modern drugs, in both its aromatic form 1 along with many, vari-
ously oxidised derivatives. Illustrative of this is the structure of 6-
azauracil 2, which exhibits growth inhibition in many organisms as
ease of synthesis and the incorporation of a pendant amino group
as an additional hydrogen-bonding centre. On the other hand, dis-
tinguishing between the multiple nucleophilic centres was clearly
going to present something of a challenge.
In general, most synthetic approaches to 1,2,4-triazines rely on
imine/enamine formation between a carbonyl and amino group; in
1
well as anti-viral activity; in addition, the 1,2,4-triazine nucleus
2
forms a crucial part of many herbicides and insecticides (Fig. 1).
The impact of such triazine derivatives (e.g., 3) has also been
the present case, suitable precursors 4 are derived from an a-keto-
3,4
5–8
significant in the anti-cancer area,
antiproliferation, and anti-inflammation, including COX-2 inhi-
in kinase inhibition,
acid 5 and thiocarbonylhydrazide 6 (Fig. 2). Additional simplicity is
added by formation of the former keto-acid from N-benzoyl glycine
7 (hippuric acid) by sequential dehydrative cyclisation and con-
densation with benzaldehyde to give the readily isolated azlactone
8. This is then hydrolysed to give the keto-acid salt 9, which is con-
densed in situ with the hydrazide 6. Again, work-up is simple and
the overall yield acceptable, despite the number of individual steps
involved (Scheme 1).
The present studies began with attempts to selectively alkylate
the triazinone 10 using allylic halides, so that an additional func-
tional group would be introduced. Initial attempts using acetoni-
trile as the solvent, potassium carbonate as the base and
methallyl chloride as the alkylating agent gave mixtures (ca. 3:1)
of the S- and N-alkyl derivatives 11 and 12 (Scheme 2).
9
10
bitory properties comparable to the well established drug cele-
coxib1
1
and non-dopaminergenic therapy for Parkinson’s
1
2,13
disease.
The parent triazine nucleus is also at the core of a ser-
ies of platinum(II) complexes having antimicrobial and antiviral
1
4
properties, while some benzotriazines are active against age-
15
related macular degeneration and compounds based on a pyrim-
1
6
idotriazine unit are capable of lowering plasma glucose levels.
The high nitrogen content of 1,2,4-triazines, along with the
incorporation of other substituents, leads to compounds which
should be able to readily form many hydrogen bonds, suggesting
a considerable potential for drug development in this area. With
this in mind, we embarked upon a project to discover new ways
in which the amino-triazin-dione nucleus 4 (Fig. 2) could be
homologated using efficient and versatile methodology. The per-
The separable products 11 and 12 were readily distinguished by
their NMR data: the S-alkylated products such as 11 showed S-
H C
methylene resonances in the range d 3.75–4.10 and d 29–
3
6 ppm whereas in the corresponding N-alkylated products,
⇑
Corresponding author.
E-mail address: knightdw@cardiff.ac.uk (D.W. Knight).
http://dx.doi.org/10.1016/j.tetlet.2016.03.065
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

2
216
A. M. Ghanim et al. / Tetrahedron Letters 57 (2016) 2215–2218
NH
2
O
2
CO H
N
PhCHO, Ac O
Ph
N
2
O
O
N
N
N
K CO , 100 oC, 1 h
N
N
N
NH
HN
2
3
N
HO
Ph
85%
Ph
N
O
N
H
O
O
7
8
1
2
3
HO
OH
2
0% aq. NaOH,
2
H N
NH
reflux, 2.5 h.
Figure 1. The 1,2,4-triazine nucleus and modifications.
HN
NH
S
6
N
Ph
NH
2
O
Ph
including 12, such resonances occurred in the ranges d
and d 60–69 ppm, respectively.
H
5.0–6.2
O
N
NH
S
CO
2
AcOH, reflux
5%
2
C
6
Fortunately, a brief solvent study established that substituting
:1 aqueous ethanol for acetonitrile resulted in complete selectiv-
10
9
1
Scheme 1. Synthesis of the starting material 10.
ity in favour of the S-alkylated product 11. This had good levels of
both chemical yields and regioselectivity for a range of primary
allylic halides, as set out in Table 1.18 No traces of N-alkylated
products arising from attack at the pendant N-amino group were
ever observed.
Having achieved this first objective, we then wondered if the
corresponding N-alkylated derivatives [cf. 12] could be obtained
by carrying out a thio-Claisen rearrangement19 of the initial ally-
lated products 13, without any interference from the pendant
Ph
O
Ph
O
Ph
O
N
N
N
N
N
N
NH
MeCN
N
N
+
S
S
S
NH2
NH2
NH2
~
3:1
Cl
1
0
11
12
amino group, which potentially could attack the new allyl group
Scheme 2. Initial alkylation attempt in MeCN.
0
by an S
N
2 mechanism. Initially, we examined purely thermal acti-
vation, the simplest way in which such rearrangements can be trig-
gered. It was soon established that relatively high temperatures
were required to trigger such thio-Claisen rearrangements with
prolonged heating in xylene at 120–140 °C delivering reasonable
isolated yields of the N-allylated products 14a–g (Table 2).20 How-
ever, we were concerned that prolonged exposure to such high
temperatures could preclude the use of more sensitive substrates
in future studies.
(tosyl chloride, CH Cl , Et N or pyridine) and to similar reactions
2
2
3
with chloroformates. However, we were successful in adding a
benzyl group by exposing precursors 13f,g to benzyl bromide in
aqueous ethanol containing 1.5 equiv of potassium hydroxide
(Scheme 4).
Despite the presence of what should be a readily protonated
amino group in both the initial precursors 13f,g and the N-benzy-
lated derivatives 16a,b, we examined the possibility of carrying out
acid-catalysed cyclisations of such substrates on the grounds that
these all also contain easily protonated side chains, which could
result in the formation of a tertiary carbenium ion. We also
included the homologous prenylated precursor 13h in this group
for the same reasons. We observed complete disappearance of all
these precursors when exposed to an equivalent of trifluo-
romethanesulfonic (triflic) acid in toluene at reflux for 1 h.
Milder conditions are available by using a palladium-based cat-
alyst to induce such rearrangements.21 We were pleased to find
that these were successful when the precursors 13 were heated
at reflux in dry tetrahydrofuran for somewhat briefer periods
2
2
(
Table 2). Isolated yields were generally higher or at least compa-
rable with the purely thermal procedure, except in the two exam-
ples where the rearrangement involved migration of a 1,1-
disubstituted alkene (entries f, g). Various attempts to improve
such returns by using higher boiling ether solvents failed. At pre-
sent, it is not clear why these two cases were inefficient. The one
exception to the foregoing positive results was the complete failure
of the prenyl-substituted derivative 13h to undergo rearrangement
using either the purely thermal or the palladium-catalysed method
to give the isomeric species 15 (Scheme 3). Excessive steric
requirements may be responsible for this.
2
4
In the case of precursor 16a, the product was separated by
1
column chromatography in 80% yield. H NMR data revealed the
disappearance of the terminal alkene protons and clearly showed
the continued presence of an NH group as a triplet but which
was shifted from d 5.37 to d 5.83, together with a six-proton res-
H
H
onance at dH 1.46, due to freely rotating geminal methyl groups
3
attached to an sp carbon. Crucially, two new resonances at dH
Having succeeded in alkylating both the sulfur and the ring
nitrogen centres, we then tried to derivatize the pendant amino
group in the initial alkylation products 13 in anticipation of being
able to effect acid-catalysed cyclisation of such modified amino
groups onto the newly introduced alkene side chains.23
We were surprised to find that attempts to add typical amine
protecting groups to this likely reactive amine group, which can
be considered as a monoacylated hydrazine functional group, were
unsuccessful. Substrates including the S-allyl and S-cinnamyl
derivatives 13a,b proved inert to ‘standard’ tosylation conditions
3.02 (2H, d, J = 9.1 Hz) and dH 0.98 (1H, t, J = 9.1 Hz) pointed to
the presence of a new CH SH thiol group and hence to the forma-
2
tion of the rearranged structure 20c, the origin of which is sug-
gested in Scheme 5.
As anticipated, an initial protonation would give rise to a ter-
tiary carbenium ion 17, trapping of which by a ring imine nitrogen
would then lead to the iminium species 18, stabilised by a number
of resonance forms, which could then be neutralised by addition of
adventitious water to give a hemiacetal species 19. This would
then collapse to give the observed products 20. Throughout this
pathway, it is likely that the benzylamine group is also protonated;
this feature has been omitted for clarity.
R
O
N
N
R
O
O
H
2
N
This rearrangement is general for this structural type, at least in
the case of the five substrates tested [13f,g,h; 16a,b], as set out in
Table 3. The yields quoted are for reactions which were followed
by TLC until complete disappearance of the starting material.
Lower temperatures, such as that of refluxing dichloromethane,
were insufficient to trigger the rearrangement. In the context of
NH
NH
+
S
OH
HN
NH
S
NH
2
2
4
5
6
Figure 2. 1,2,4-Triazin-3-thiono-5-one synthesis.

A. M. Ghanim et al. / Tetrahedron Letters 57 (2016) 2215–2218
2217
Table 1
Ph
Ph
O
Selective S-alkylation of 3-thioxo-1,2,4-triazin-5-one 10
N
N
N
N
SH
N
TfOH (1 eq.)
R3
N
R1
X
R1
O
S
toluene, reflux, 1 h
O
N
N
N
N
R3
S
NHBn
BnHN
Ph
NH
R2
Ph
N
R2
1
6a
O
S
O
20c
1
2
:1 aq. EtOH,
0 C, 2-8 h
NH
2
O
NH
2
TfOH
1
0
13
R3
Ph
O
Ph
Ph
O
R1
R2
Entry
X
Time Yield (13; %)
N
N
N
N
N
N
S
N
a
b
c
d
e
f
H
Ph
Me
H
H
H
H
H
Br
Cl
Cl
Br
Br
Cl
2 h
8 h
8 h
4 h
4 h
2 h
4 h
8 h
85
O
BnHN
N
S
N
S
75
H
OH
NHBn
O
H
BnHN
H
H
73
1
7
18
19
Pr
H
H
64
Bu
H
H
77
Scheme 5. The structure of the acid-catalysed rearrangement product 20c and a
proposed mechanism for its formation.
H
Me
Ph
H
80 (= 11)
85
Bra)
g
H
H
h
Me
Me
Br
80
aContained ca. 20% of the corresponding (unreactive) vinyl bromide,
Table 3
Acid-catalysed rearrangements of 13f,g,h; 16a,b
Ph
(E)-1-bromo-2-phenyl-1-propane, the presence of which was com-
Ph
R
2
pensated for by using 1.3 equiv of the isomeric mixture.
N
N
R2
N
N
SH
1
eq. TfOH
N
N
toluene, reflux, 1 h.
O
S
O
O
1
1
NHR
NHR
13f,g,h; 16a,b.
20
Table 2
Precursor
R1
R2
Yield 20
Thermal and Pd-catalysed thio-Claisen rearrangements
1
3f
H
H
Me
Ph
Me
Ph
a) 70%
b) 75%
c) 80%
d) 67%
e) 80%
Ph
xylene (0.4 mmol ml-1),
Ph
R1
S
R2
S
13g
16a
N
N
120-140 o
N
N
N
R1
C
N
R2
Bn
Bn
O
or 10 mol% PdCl
2
(PhCN)
2
,
O
1
1
6b
3h
NH
2
THF, reflux
NH
2
1
3
14
Ph
O
Ph
O
N
N
N
N
N
N
SH
Thermal
Pd-catalysed
R1
R2
S
O
Entry
Time/temp. Yield 14
Time Yield 14
NH
2
NH2
a
b
c
d
e
f
H
H
H
H
H
H
14 h; 140 o
14 h; 130 o
C
C
66%
40%
33%
50%
25%
25%
50%
12 h
12 h
8 h
78%
50%
86%
50%
84%
15%
15%
Ph
Me
5 h; 130 o
14 h; 130 o
14 h; 120 o
C
the aims of the present project, this finding provides a solution to
the problem of obtaining alkylated derivatives having a tertiary
centre adjacent to the nitrogen atom and should be extendable
to the elaboration of many similar derivatives. The incorporation
of the thiol group is, of course, also very useful as this could be
used in many ways to introduce additional substituents.
We have therefore established highly selective methods for the
selective S- and N-alkylation of this type of 1,2,4-triazine deriva-
tives and have also discovered a new type of acid-catalysed rear-
rangement, which provides an approach to highly substituted
products which would not be available from direct alkylation
reactions.
Pr (Z-13)
C
C
C
C
8 h
Bu
H
8 h
Me 14 h; 130 o
Ph 14 h; 120 o
14 h
14 h
g
H
Ph
O
Ph
O
N
N
xylene, 120-140 o
N
C
N
S
N
or PdCl (PhCN)2
2
N
NH2
S
NH
2
Acknowledgement
1
3h
15
We are grateful to the Ministry of Higher Education in Egypt for
financial support (to A.M.G.).
Scheme 3. Failure of a distally-substituted example.
References and notes
Ph
Ph
O
1
.
Archambault, J.; Lacroute, F.; Ruet, A.; Friesen, J. D. Mol. Cell. Biol. 1992, 12,
4142–4152.
N
N
R
S
N
N
R
S
2
PhCH Br, (1.2 eq.)
N
N
2
3
.
.
Baez, M. E.; Zincker, J. Biol. Soc. Chil. Quim. 1999, 44, 357–366.
Zeman, E. M.; Baker, M. A.; Lemmon, M. J.; Pearson, C. I.; Adams, J. A.; Brown, J.
M.; Lee, W. W.; Tracy, M. Int. J. Radiat. Oncol. Biol. Phys. 1989, 16, 977–981;
Johnson, K. M.; Parsons, Z. D.; Barnes, C. L.; Gates, K. S. J. Org. Chem. 2014, 79,
7520–7531. and references therein.
KOH (1.5 eq.),
O
o
1
8 h, 20
C
NH
2
NHBn
1
3f,g
16a; R = Me (70%)
b; R = Ph (60%)
4
.
Ashour, H. M.; El-Wakil, M. H.; Khalil, M. A.; Ismail, K. A.; Labouta, I. M. Med.
Chem. Res. 2013, 22, 1909–1924.
Scheme 4. N-benzylation of the 4-amino group.

2
218
A. M. Ghanim et al. / Tetrahedron Letters 57 (2016) 2215–2218
5
.
.
.
Ott, G. R.; Wells, G. J.; Thieu, T. V.; Quail, M. R.; Lisko, J. G.; Mesaros, E. F.;
20. General procedure for the thermal Claisen rearrangements: In a flame dried flask,
a 3-(ally1thio)1,2,4-triazin-5-ones 13 (0.5 g) were dissolved in xylene (5 mL)
Gingrich, D. E.; Ghose, A. K.; Wan, W.; Lu, L.; Cheng, M.; Albom, M. S.; Angeles,
T. S.; Huang, Z.; Aimone, L. D.; Ator, M. A.; Ruggeri, B. A.; Dorsey, B. D. J. Med.
Chem. 2011, 54, 6328–6341.
Wrobleski, S. T.; Lin, S.; Hynes, J.; Wu, H.; Pitt, S.; Shen, D. R.; Zhang, R.; Gillooly,
K. M.; Shuster, D. J.; McIntyre, K. W.; Doweyko, A. M.; Kish, K. F.; Tredup, J. A.;
Duke, G. J.; Sack, J. S.; McKinnon, M.; Dodd, J.; Barrish, J. C.; Schieven, G. L.;
Leftheris, K. Bioorg. Med. Chem. 2008, 18, 2739–2744.
2
and the solution refluxed under N for 5–14 h then allowed to cool to room
temperature then the solvent evaporated in vacuo to afford the desired N-allyl
derivative 14 after flash column chromatographic purification (petroleum
ether/ethyl acetate 9:1). 4-Amino-6-benzyl-2-(2-allyl)-3-thioxo-3,4-dihydro-
6
7
1,2,4-triazin-5(2H)-one 14a was obtained as a yellow oil, (0.33 g, 66%). 1
H
NMR (400 MHz; CDC1
5.90 (1H, m, ACH@), 5.30–5.24 (2H, m, @CH
NCH ), 3.93 (2H, s, CH
Ph); 13C NMR (125 MHz; CDCl
(C@O), 145.9 (CAC@N), 135.5 (ArAC), 130.1 (CH@), 129.3, 128.7, 127.2
3
) d 7.28–7.17 (5H, m, 5 ꢀ ArAH), 6.28 (2H, s, NH
), 5.00 (2H, app. d, J = 6.1 Hz,
): d 167.9 (C@S), 147.3
2
), 5.99–
Khoshneviszadeh, M.; Ghahremani, M. H.; Foroumadi, A.; Miri, R.; Firuzi, O.;
Madadkar-Sobhani, A.; Edraki, N.; Parsa, M.; Shafiee, A. Bioorg. Med. Chem.
2
2
2
3
2
013, 21, 6708–6717.
ꢁ
1
8
.
.
Ramasamy, K.; Ugarkar, B. G.; Mckernan, P. A.; Robins, R. K.; Revankar, G. R. J.
Med. Chem. 1986, 29, 2231–2235.
Diana, P.; Barraja, P.; Lauria, A.; Montalbano, A.; Almerico, M.; Dattolo, G.;
Cirrincione, G. Eur. J. Med. Chem. 2002, 37, 267–272.
(3 ꢀ ArACH), 120.1 (@CH
3335, 3306, 3088, 3065, 3028, 2937, 2922, 1682, 1446, 1423, 1273, 931, 730;
HRMS (EI+) m/z calcd for C13 OS = 274.0888; found 274.0878.
2 2 2
), 60.3 (NACH A), 36.7 (CH APh); IR(neat) m/cm :
9
14 4
H N
21. Meyers, C. Y.; Rinaldi, C.; Bonoli, L. J. Org. Chem. 1963, 28, 2440–2442;
Takahashi, H.; Oshima, K.; Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc. 1973, 95,
5803–5804; Gu, X.; Cowell, S.; Ying, J.; Tang, X.; Hruby, V. J. Tetrahedron Lett.
2003, 44, 5863–5866; Liu, Z.; Qu, H.; Gu, X.; Min, B. J.; Nichol, G. S.; Nyberg, J.;
Hruby, V. J. Org. Lett. 2008, 10, 4105–4108; For a recent review, see Majumdar,
K. C.; Samanta, S.; Chattapadhyay, B.; Pal, N. Curr. Org. Synth. 2012, 9, 851–872.
22. General procedure for the Pd(II)-catalyzed Claisen rearrangement: To a solution of
a 3-(allylthio)-1,2,4-triazin-5-one 13 (1 equiv) in dry tetrahydrofuran (5 mL
1
0. Liu, C.; Lin, J.; Wrobleski, S. T.; Lin, S.; Hynes, J.; Wu, H.; Dyckman, A. J.; Li, T.;
Wityak, J.; Gillooly, K. M.; Pitt, S.; Shen, D. R.; Zhang, R. F.; McIntyre, K. W.;
Salter-Cid, L.; Shuster, D. J.; Zhang, H.; Marathe, P. H.; Doweyko, A. M.; Sack, J.
S.; Kiefer, S. E.; Kish, K. F.; Newitt, J. a.; McKinnon, M.; Dodd, J. H.; Barrish, J. C.;
Schieven, G. L.; Leftheris, K. J. Med. Chem. 2010, 53, 6629–6639.
1
1. Irannejad, H.; Kebriaieezadeh, A.; Zarghi, A.; Montazer-Sadegh, F.; Shafiee, A.;
Assadieskandar, A.; Amini, M. Bioorg. Med. Chem. 2014, 22, 865–873.
2. Congreve, M.; Andrews, S. P.; Doré, A. S.; Hollenstein, K.; Hurrell, E.; Langmead,
C. J.; Mason, J. S.; Ng, I. W.; Tehan, B.; Zhukov, A.; Weir, M.; Marshall, F. H. J.
Med. Chem. 2012, 55, 1898–1903.
1
per mmol), bis(benzonitrile)-palladium(II) chloride [PdCl
was added and the resulting solution stirred and heated to reflux under N
2
(PhCN)
2
)] (10 mol %)
for
2
the time indicated in Table 2. After evaporation of the solvent, the residue was
directly subjected to column purification (petroleum ether/ethyl acetate 9:1;
silica gel) to obtain the corresponding N-allyl-1,2,4-triazin-5-one 14.
1
3. Kumar, J. S. D.; Majo, V. J.; Hsiung, S.; Millak, M. S.; Liu, K.; Tamir, H. J. Med.
Chem. 2006, 49, 125–134.
1
4. Vzorov, A. N.; Bhattacharyya, D.; Marzilli, L. G.; Compans, R. W. Antiviral Res.
2 2
Specifically, the S-allyl derivative 13a (0.50 g, 1.8 mmol) and PdCl (PhCN)
2
005, 65, 57–67.
(0.069 g, 0.18 mmol) were reacted for 12 h to give 4-amino-6-benzyl-2-(2-
allyl)-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one 14a as a yellow oil (0.40 g,
78%), which exhibited spectroscopic and analytical data identical to those
reported above.
1
1
5. Palanki, M.; Akiyama, H. J. Med. Chem. 2008, 51, 1546–1559.
6. Guertin, K. R.; Setti, L.; Qi, L.; Dunsdon, R. M.; Dymock, B. W.; Jones, P. S.;
Overton, H.; Taylor, M.; Williams, G.; Sergi, J. A.; Wang, K.; Peng, Y.; Renzetti,
M.; Boyce, R.; Falcioni, F.; Garippa, R.; Olivier, A. R. Bioorg. Med. Chem. Lett.
23. Henderson, L.; Knight, D. W.; Williams, A. C. Tetrahedron Lett. 2012, 53, 4657–
4660; Henderson, L.; Knight, D. W.; Williams, A. C. Synlett 2012, 1667–1669.
24. General procedure for acid-catalysed rearrangements: In flame dried flask, a 3-
(ally1thio)-1,2,4-triazin-5-one 13f,h or 16a,b,h (1 equiv) was dissolved in dry
toluene (5 mL per mmol) and the stirred solution cooled to 0 °C.
Trifluoromethanesulfonic acid (1 equiv) was added via syringe and the flask
placed in an oil bath, which was then heated to 110 °C for 1–4 h. The cooled
solution was diluted with ethyl acetate then neutralised with saturated
aqueous potassium carbonate (10 mL). The aqueous phase was extracted with
ethyl acetate (3 ꢀ 10 mL) and the combined extracts dried over magnesium
sulphate then filtered and evaporated. The crude residue was separated by
flash chromatography (petroleum ether/ethyl acetate 8:2). 4-Amino-6-benzyl-
2-(1-mercapto-2-methylpropan-2-yl)-1,2,4-triazine-3,5(2H,4H)-dione 20a was
2
003, 13, 2895–2898.
1
7. Eid, M. M.; Hassan, R. A.; Kadry, A. M. Pharmazie 1988, 43, 166–167; Shinkai, H.;
Toi, K.; Kumashiro, I.; Seto, Y.; Fukuma, M.; Dan, K.; Toyoshima, S. J. Med. Chem.
1
988, 31, 2092–2097.
1
8. A typical alkylation procedure of precursor 10 is as follows: The triazine 10
(
(
0.50 g, 2.14 mmol, 1 equiv) was added to a solution of potassium carbonate
0.45 g, 3.21 mmol, 1.5 equiv) in water and ethanol (1:1; 30 mL) and the
resulting solution stirred for 10 min. The alkylating agent (2.35 mmol,
.1 equiv) was then added and the reaction stirred for 2-8 h at ambient
1
temperature. The resulting precipitate was filtered off and washed with water
then re-crystallised from ethanol. 3-(Allylthio)-4-amino-6-benzyl-1,2,4-triazin-5
1
(
4H)-one 13a was isolated as colourless crystals (0.49 g, 85%), mp 105 °C;
NMR (400 MHz, CDCl
0.0, 7.0 Hz, ACH@), 5.29 (1H, app. dd, J = 17.0, 1.3 Hz, @CH
dd, J = 10.0, 1.1 Hz, @CH ), 4.74 (s, 2H, NH ), 4.02 (2H, s, CH Ph), 3.76 (2H, app.
); C NMR (125 MHz; CDCl ): 159.9 (C@O), 155.6 (SAC@N),
52.1 (CAC@N), 135.9 (ArAC), 131.7 (CH@), 129.3, 128.4, 126.8 (3 ꢀ ArACH),
H
thus obtained as a yellow oil (0.35 g, 70%). 1H NMR (400 MHz; CDCl
7.26–7.16 (5H, m, 5 ꢀ Ar-H), 5.24 (2H, s, NH ), 3.89 (2H, s, CH Ph), 3.09 (2H, d,
J = 9.0 Hz, CH ), 1.18 (1H, t, J = 9.0 Hz, SH); C NMR
SH), 1.53 (6H, s, 2 ꢀ CH
(125 MHz/CDCl
3
): d 7.30–7.10 (5H, m, 5 ꢀ ArAH), 5.90 (1H, ddt, J = 17.0,
3
): d
1
2
), 5.13 (1H, app.
2
2
13
2
2
2
2
3
1
3
d, J = 7.0 Hz, SCH
2
3
3
): 152.5, 146.5 (2 ꢀ C@O), 141.2 (C@N), 136.2 (ArAC), 129.3,
1
1
3
128.5, 126.9 (3 ꢀ ArACH), 67.6 (C(CH
3 2 2 2
) ), 36.7 (PhCH ), 34.1 (SCH ), 25.7
ꢁ
1
ꢁ1
19.3 (@CH
022, 2933, 1666, 1597, 1450, 1423, 1215, 925, 717; HRMS (APCI+) m/z calcd
OS [M+H]+ = 275.0967; found 275.0969.
2
), 37.2 (CH
2
Ph), 33.8 (CH
2
S); IR(neat)
m
/cm 3267, 3203, 3182,
(2 ꢀ CH
3
); IR (neat)
m
/cm : 3332, 3234, 3053, 3028, 2976, 2935, 1710, 1645,
+
1438, 1263, 1136; HRMS (EI+) m/z calcd forC14
H
N
17 4
O
2
S [MꢁH] = 305.1072;
for C13
H
N
15 4
found 305.1070.
1
9. Mikami, K.; Takahashi, K.; Nakai, T. Tetrahedron Lett. 1987, 28, 5879–5882;
Tamaru, Y.; Kagotani, M.; Yoshida, Z. Tetrahedron Lett. 1981, 22, 4245–4248;
Tamaru, Y.; Kagotani, M.; Yoshida, Z. J. Org. Chem. 1980, 45, 5221–5223.