Dihydro-1,2,4-triazin-6(1H)-ones. II synthesis of several methylated 3-phenyl-4,5-dihydro-1,2,4-triazin-6(1H)-ones

Article abstract of DOI:10.1071/CH99012

Novel syntheses of 4,5-dihydro-1,2,4-triazin-6(1H)-ones were developed by use of imidoyl chlorides. The overall yield of 4,5-dihydro-1,2,4-triazin-6(1H)-ones prepared from amino acid imidates and hydrazines was improved by the development of a much more efficient synthesis of the imidates. The new 1,2-, 1,4- and 5,5-dimethyl dihydro-1,2,4-triazin-6(1H)-ones have been synthesized by cyclocondensation/cycloaddition pathways. Base-catalysed methylation of 3-phenyl-4,5-dihydro-1,2,4-triazin-6(1H)-one (15) gave the 1-methylated derivative (8); under similar conditions 2-methyl-3-phenyl-2,5-dihydro-1,2,4-triazin-6(1H)-one (9) afforded the 1,2-dimethyl derivative (7).

Full text of DOI:10.1071/CH99012

C S I R O P U B L I S H I N G
Australian Journal
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Volume 52, 1999
© CSIRO Australia 1999
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Aust. J. Chem., 1999, 52, 379–385
.
Dihydro-1,2,4-triazin-6(1H )-ones. II
Synthesis of Several Methylated 3-Phenyl-
4,5-dihydro-1,2,4-triazin-6(1H )-ones
David J. Collins,A Timothy C. Hughes A,B and Wynona M. Johnson B
A
Department of Chemistry, Monash University, Clayton, Vic. 3168.
CSIRO Molecular Science, Private Bag 10, Rosebank MDC, Clayton, Vic. 3169.
B
Novel syntheses of 4,5-dihydro-1,2,4-triazin-6(1H )-ones were developed by use of imidoyl chlorides. The
overall yield of 4,5-dihydro-1,2,4-triazin-6(1H )-ones prepared from amino acid imidates and hydrazines
was improved by the development of a much more e cient synthesis of the imidates. The new 1,2-, 1,4- and
5,5-dimethyl dihydro-1,2,4-triazin-6(1H )-ones have been synthesized by cyclocondensation/cycloaddition
pathways. Base-catalysed methylation of 3-phenyl-4,5-dihydro-1,2,4-triazin-6(1H )-one (15) gave the 1-
methylated derivative (8); under similar conditions 2-methyl-3-phenyl-2,5-dihydro-1,2,4-triazin-6(1H )-one
(9) a orded the 1,2-dimethyl derivative (7).
Introduction
the amino acid ester hydrochloride salt (1a), methyl
benzimidate hydrochloride (2) and 1 equiv. of ‘lab-
oratory grade’ triethylamine in dichloromethane was
stirred at room temperature overnight to give the
corresponding amino acid imidate (5a) in 60% yield
and 80% purity. When 2 equiv. of triethylamine were
used, the product mixture contained some diaddition
material (4). No reaction took place under anhydrous
conditions, contrary to a report by Lerestif et al.5 who
In some of the literature on dihydro-1,2,4-triazin-
6(1H )-ones doubts are raised as to whether some of the
compounds described are actually imidazolones, and/or
are di erent regioisomers to the one(s) described.1 We
have found that 4,5-dihydro-1,2,4-triazin-6(1H )-ones
have potential as crop protection agents and it was
advantageous to develop unambiguous synthetic routes
to a wide range of derivatives. Very few of the reported
syntheses of dihydro-1,2,4-triazin-6(1H )-ones are for
compounds with substituents attached at positions
other than C 3 or C 5. Varying the substituents at
C 3 and C 5 is relatively easy, since these positions
originate from a modi ed -amino acid. Those few
examples2 of dihydro-1,2,4-triazin-6(1H )-ones having
N- or O-substituents have been prepared by ambiguous
routes, with the exception of the work by El-Abadelah
et al.3 who reported the addition of nitrile imines
to amino acid esters. It was therefore desirable to
develop new routes for the regiospeci cally substituted
dihydro-1,2,4-triazin-6(1H )-ones.
Results and Discussion
Synthesis of Amino Acid Imidates (5)
The use of imidate esters (5) to prepare 4,5-dihydro-
1,2,4-triazin-6(1H )-ones has been demonstrated by
Kjaer4 and Camparini et al.2 Imidate derivatives
of the type (5) can be prepared from the reaction
(Scheme 1) of the corresponding amino acid ester
hydrochloride salts (1a,b) with triethylamine and the
imidate ester hydrochloride salt (2).5 A mixture of
Part I, Aust. J. Chem., 1996, 49, 463.
Manuscript received 29 January 1999
᭧ CSIRO 1999
0004-9425/99/050379$ 05.00
10.1071/CH99012

380
D. J. Collins, T. C. Hughes and W. M. Johnson
claimed that anhydrous triethylamine was required.
Compound (5b) was also prepared in this manner.
However, amino acid imidates (5) are usually pre-
pared by the general procedure of Schmidt6 or by
a modi cation7 in which an aqueous solution of the
amino acid ester hydrochloride (1a–c) is shaken with a
diethyl ether solution of the imidate ester (3) (Scheme
1). When ethyl glycinate hydrochloride (1a) was used,
the yield of the desired imidate derivative (5a) was rela-
tively low (59%) and it was accompanied by 12% of the
hydrolysis product ethyl N -benzoylglycinate (6a) and
29% of unidenti ed products. It was therefore desirable
to develop a new and improved route to this important
intermediate. 1H n.m.r. spectroscopic studies of the
reaction of (1a) with (3) were carried out in deuterated
dimethylformamide or in deuterated acetonitrile. They
showed that the reaction progressed smoothly to a
certain point, but then stopped. Prolonged reaction
times led to decomposition products and the forma-
tion of some of the diaddition product (4) (Scheme
1). Preparative scale reactions carried out in anhy-
drous dimethylformamide or N -methylpyrrolidinone
gave similar results. It appeared that there were two
factors involved: (i) the reaction reached equilibrium
in single-phase media; (ii) the chloride ion present in
the reaction may be nucleophilic enough under these
conditions to give rise to decomposition products. A
possible solution to both of these problems was to use
the p-toluenesulfonic acid salts (1d–f), rst because
the sulfonate anion is non-nucleophilic, and second, in
an appropriate solvent, the reaction could be forced
to completion by the precipitation of the insoluble
ammonium p-toluenesulfonate.
and 2-methyl-3-phenyl-2,5-dihydro-1,2,4-triazin-6(1H )-
one (9) (70%) (Scheme 2) (cf. Camparini et al.2).
These N -methyl derivatives were readily separated by
chromatography due to their surprisingly very di erent
chemical and physical properties. The 2-methyl deriva-
tive (9) was water-soluble and its infrared spectrum
showed no carbonyl absorption, while the 1-methyl
derivative (8) was not water-soluble and its infrared
spectrum showed a strong carbonyl absorption. The
2-methyl derivative (9) was shown by single-crystal
X-ray structure analysis to exist as a zwitterion in
the solid state.14 Spectroscopic analysis of (8) and (9)
showed that they were respectively identical to the
1- and 2-methyl derivatives prepared previously by
unambiguous routes.12
The ethyl glycinate p-toluenesulfonic acid salt
(1d) was prepared as described by Ueda.8 The
p-toluenesulfonic acid salt (1e) of ethyl (RS)-alaninate
and the corresponding salt (1f) of ethyl 2-amino-2-
methylpropanoate were prepared similarly.9,10
Preparation of 1,2-Dialkylated 4,5-Dihydro-1,2,4-
triazin-6(1 H)-ones
In our quest for crop protection chemicals, 1,2-
dialkylated 3-phenyl-2,5-dihydro-1,2,4-triazin-6(1H )-
ones were of particular interest because this disub-
stitution precludes aerial oxidation to a 4,5-dehydro
compound and aerial oxidation of 1,2-dialkylated tri-
azinone derivatives to 5,6-dioxo compounds is less likely
(see Scheme 4, below). The 1,2-dimethyl compound
(7) and other dialkylated analogues were therefore of
special interest. When a solution containing the freshly
prepared imidate (5a) and 1,2-dimethylhydrazine was
heated at 130 C for 2 h (Scheme 2), chromatography
of the product a orded 34% of the new 1,2-dimethyl-
3-phenyl-2,5-dihydro-1,2,4-triazin-6(1H )-one (7). It is
not clear whether the low yield was due to low conversion,
or to loss of material when the 1,2-dimethylhydrazine
dihydrochloride was neutralized with 2 equiv. of sodium
methoxide. The 1H and 13C n.m.r. spectra of (7)
showed the methyl resonances at 2 91 and 3 20, and
32 3 and 39 2, respectively, and the mass spectrum
showed the expected molecular ion.
Treatment of methyl benzimidate11 (3) with the
ethyl glycinate p-toluenesulfonic acid salt (1d) in
dichloromethane under re ux gave the desired glycine
imidate derivative (5a) in 81% yield and in greater than
97% purity (Scheme 1).12 The 13C n.m.r. spectrum
of this material was consistent with that reported by
Shi et al.13 Our new procedure also worked well for
the reaction of the p-toluenesulfonic acid salt (1e) of
ethyl (RS)-alaninate with (3), but a longer reaction
time was required (2–3 h). Hence the above procedure
constitutes an improved synthesis of imidate esters.
Preparation of 1- and 2-Alkylated 4,5-Dihydro-
1,2,4-triazin-6(1 H)-ones
Not surprisingly, the reaction of the glycine imi-
date (5a) with methylhydrazine was not regioselec-
tive, giving a mixture of the regioisomers 1-methyl-
3-phenyl-4,5-dihydro-1,2,4-triazin-6(1H )-one (8) (22%)
Ueda reported that compound (1d) was an oil. However, in our hands, it was obtained as a solid, m.p. 80 5 , which gave the
expected spectroscopic data and elemental analyses.

Dihydro-1,2,4-triazin-6(1H )-ones. II
381
Methylation of the 2-Methyltriazinone (9)
ylation of 3-phenyl-4,5-dihydro-1,2,4-triazin-6(1H )-one
(15) with sodium hydride and methyl iodide.
Although the dimethyl compound (7) could be
obtained from reaction of 1,2-dimethylhydrazine with
the glycine imidate derivative (5a), the lack of avail-
ability of alkylated hydrazines and poor yield meant
that this approach was restrictive. If the further alkyl-
ation of 2-methyl derivative (9), or other 2-substituted
analogues, proceeded regioselectively at N 1 a range
of 1,2-disubstituted derivatives of potential biologi-
cal interest would be accessible. Treatment of the
2-methyltriazinone (9) with sodium methoxide and
methyl iodide in dry methanol gave a good yield of the
1,2-dimethyl derivative (7) (Scheme 2). Indeed alkyl-
ation of 2-methyltriazinones proved to be an e cient
and general procedure for producing 1,2-disubstituted
compounds.
Synthesis of the 5,5-Dimethylated Triazinone (20)
1-Alkyl-4,5-dihydro-1,2,4-triazin-6(1H )-ones
(16)
were found to be susceptible to aerial oxidation to
the corresponding dehydro derivatives (17) and 5,6-
dioxo derivatives (18). Therefore it was necessary to
determine if the net biological activity observed for com-
pounds of type (16) was due to the parent compound or
its aerial oxidation products (Scheme 4). In this respect,
it was of interest to prepare 5,5-dimethyl-3-phenyl-
4,5-dihydro-1,2,4-triazin-6(1H )-one (20) in which aerial
oxidation at C 5 is precluded.
Compound (19), a phenolic derivative of (20), has
been reported by Chaloupka and Heimgartner,15 but
we required a synthetic route which is more direct
and more amenable to the introduction of various
substituents on the heterocyclic ring.
Synthesis of the 1,4-Dimethylated Triazinone (12)
The 1,4-dimethyl compound (12) (Scheme 3) was
prepared by means of nitrile imine chemistry. An N -
methyl nitrile imine was generated in situ by treating
the N -methyl hydrazonoyl bromide hydrobromide12
(10) with triethylamine. Cyclocondensation between
the nitrile imine and ethyl sarcosinate hydrochloride
(11) a orded, after chromatography, 1,4-dimethyl-3-
phenyl-4,5-dihydro-1,2,4-triazin-6(1H )-one (12) in 73%
yield. The 1H and 13C n.m.r. spectra of (12) showed
two methyl resonances at 2 73 and 3 23, and 35 6 and
39 1, respectively. The mass spectrum of (12) showed
the expected molecular ion. The 1,4-dimethyl derivative
(12) was also the product formed on stepwise dimeth-
Theoretically the dihydrotriazinone (20) may be pre-
pared by using the dimethyl imidate derivative (5c).
However, this intermediate was unstable and di cult
to prepare, so attention was directed to synthesis and
use of the corresponding imidoyl chloride (21).
The preparation of imidoyl halides is well docu-
mented,16 and the desired imidoyl chloride (21) was pre-
pared by a standard procedure (Scheme 5). 2-Amino-2-
methylpropanoic acid was converted into ethyl 2-amino-
2-methylpropanoate hydrochloride (1c) by treatment
with thionyl chloride and ethanol. Reaction of (1c)
with benzoyl chloride and triethylamine a orded the
N -benzoyl derivative (6c), whose physical properties
were consistent with those reported by Obrecht and
Heimgartner.17 Treatment of the amide (6c) with phos-
phorus pentachloride in carbon tetrachloride at re ux
This oxidation will be reported in detail elsewhere by Collins, D. J., Hughes, T. C., and Johnson, W. M.

382
D. J. Collins, T. C. Hughes and W. M. Johnson
for 2 h a orded a product which contained 89% of the
imidoyl chloride (21) and 11% of the starting amide
(6c) (1H and 13C n.m.r. spectroscopic analysis). The
13C n.m.r. spectrum of (21) showed no amide carbonyl
resonance at 166 6, but a new resonance at 140 8
corresponding to the imine carbon atom. Unlike its
glycine analogue (14), which is unstable and quickly
forms 5-ethoxy-2-phenyloxazole (13) (Scheme 3), the
dimethyl imidoyl chloride (21) was relatively stable.
ve possible monomethylation products of 3-phenyl-4,5-
dihydro-1,2,4-triazin-6(1H )-one (15), namely, (8), (9)
and (22)–(24). We found that treatment of compound
(15) with 1 mole equiv. of each of sodium hydride
and methyl iodide at 0 C gave a single product in
93% yield (Scheme 3). This was identi ed as the
1-methyl derivative (8) by comparison of its spectral
data and melting point with those of an authentic
sample prepared by an unambiguous route.12
Conclusion
New routes to the dihydro-1,2,4-triazin-6(1H )-ones
were developed by use of imidoyl chlorides. These
compounds allowed a wider range of hydrazine deriva-
tives to be cyclocondensed to form the desired ring
compounds. An improved synthesis of amino acid
ester derived imidates was developed by use of the
corresponding p-toluenesulfonic acid salts under anhy-
drous conditions. This procedure avoided formation
of hydrolysis and diaddition products observed when
the conventional route was used. The new 1,2-, 1,4-
and 5,5-dimethyl dihydro-1,2,4-triazin-6(1H )-ones have
been synthesized by cyclocondensation/cycloaddition
pathways. Methylation of 3-phenyl-4,5-dihydro-1,2,4-
triazin-6(1H )-one (15) with methyl iodide and sodium
hydride a orded the 1-methyl derivative (8) as the sole
product. The position of alkylation was con rmed by
comparison of the product formed with the ve possible
monomethylation products which had been previously
unambiguously prepared. Methylation of the 2-methyl
derivative (9) a orded the 1,2-dimethyl derivative (7)
in a better yield than that obtained by reaction of
the imidate (5a) and 1,2-dimethylhydrazine.
Reaction of an excess of hydrazine hydrate with the
freshly prepared imidoyl chloride (21) in anhydrous
dichloromethane gave the new 5,5-dimethyl-3-phenyl-
4,5-dihydro-1,2,4-triazin-6(1H )-one (20) in 92% yield.
1
The H and 13C n.m.r. spectra of (20) showed methyl
resonances at 1 41 and 25 0, respectively.
New Synthesis of the 3-Phenyl
Dihydrotriazinone (15)
The imidoyl chloride (14), previously synthesized
by us,12 is a highly reactive N -acyl amino acid
equivalent which was expected to undergo cyclocon-
densation with a wide range of hydrazine deriva-
tives to generate dihydro-1,2,4-triazin-6(1H )-ones. To
our surprise, the highly exothermic reaction of the
imidoyl chloride (14) in anhydrous diethyl ether/
methanol with hydrazine monohydrate at room temper-
ature gave poor yields (16–19%) of 3-phenyl-4,5-dihydro-
1,2,4-triazin-6(1H )-one (15), the major product being
5-ethoxy-2-phenyloxazole (13) (Scheme 3). However,
when the reaction was repeated at 78 C the yield of
3-phenyl-4,5-dihydro-1,2,4-triazin-6(1H )-one (15) was
much better (59%). The melting point and spectro-
scopic data were consistent with those reported by
Andersen et al.18
Experimental
Experimental and instrumental details were as described
previously.12
The p-Toluenesulfonic Acid Salt (1d) of Ethyl Glycinate
A mixture of glycine (5 00 g, 66 5 mmol) and ethyl p-
toluenesulfonate (14 8 g, 73 3 mmol) was suspended in anhy-
drous ethanol (150 ml) and heated under re ux for 36 h.
Evaporation of the solvent under reduced pressure gave a white
solid which was suspended in anhydrous diethyl ether (200 ml)
and ltered to give the salt (1d) as a white solid (20 34 g,
100%), m.p. 80 5 (lit.8 oil) (Found: C, 47 9; H, 6 2; N,
Methylation of the 3-Phenyl Dihydrotriazinone (15)
While 1,2,4-triazin-5(4H )-ones feature prominently
in the reviews19 of the alkylation of 1,2,4-triazine
derivatives, the only papers found on the alkylation of
1,2,4-triazin-6(1H )-ones or their derivatives are those
by Prokofeva et al.20 and Camparini et al.2 There are
5 2. Calc. for C11H17NO5S: C, 47 9; H, 6 2; N, 5 1%).
(KBr) 3006s(br), 1746s, 1179s(br) cm
max
.
1H n.m.r. 1 15, t,
1
J 7 14 Hz, OCH2CH3; 2 32, s, ArCH3; 3 66, br q, J 6 9 Hz,
+NH3CH2; 4 03, q, J 7 2 Hz, OCH2CH3; 7 08, d, J 8 2 Hz,
H 30 and H 50; 7 68, d, J 8 2 Hz, H 20 and H 60; 7 95, br t,

Dihydro-1,2,4-triazin-6(1H )-ones. II
383
J 6 9 Hz, +NH3CH2. 13C n.m.r. 13 75, OCH2CH3; 21 3,
ArCH3; 40 5, NCH2; 62 2, OCH2CH3; 126 0, C 20, C 60 or
C 30, C 50; 128 9, C 20, C 60 or C 30, C 50; 140 7, C 10 or C 40;
144 6, C 10 or C 40; 167 3, C=O.
idate (3) (3 00 g, 22 2 mmol) in dry dichloromethane (30 ml).
The mixture was heated under re ux for 3 h under an argon
atmosphere. During this time a white precipitate of ammo-
nium p-toluenesulfonate formed. The mixture was cooled and
then poured onto a short column of silica gel. Elution with
dichloromethane a orded (5b) (3 77 g, 90%) as a colourless
oil. The crude product was used immediately without further
puri cation (Found: [M+1]+ , 236 130. C13H18NO3 requires
The p-Toluenesulfonic Acid Salt (1e) of Ethyl (RS)-Alaninate
The p-toluenesulfonic acid salt (1e) of ethyl (RS)-alaninate
was prepared from (RS)-alanine by the same procedure as that
used to prepare the analogous salt (1d) above. A mixture of
(RS)-alanine (20 00 g, 224 mmol) and ethyl p-toluenesulfonate
(49 4 g, 247 mmol) was suspended in anhydrous ethanol (400 ml)
and heated under re ux for 36 h. Evaporation under reduced
pressure gave a white solid which was suspended in anhydrous
diethyl ether (200 ml) and ltered to give the salt (1e) (64 6
g, 99%) as a white solid. A sample was recrystallized from
[M+1]+ , 236 129).
1278s, 1199s, 1125s, 1051m, 889m cm
( lm) 2986m, 1739s, 1668s, 1447m,
1
max
.
1H n.m.r. 1 22,
t, J 7 0 Hz, CH2CH3; 1 32, d, J 6 8 Hz, CHCH3; 3 85, s,
OCH3; 3 98–4 19, m, CH2CH3, CHCH3; 7 25–7 43, m, Ar.
13C n.m.r.
14 0, CH2CH3; 20 0, CHCH3; 53 3, CHCH3;
57 2, OCH3; 60 5, CH2CH3; 127 4, C 20, C 60 or C 30, C 50;
128 3, C 20, C 60 or C 30, C 50; 129 4, C 40; 131 9, C 10; 162 9,
C=N; 173 4, C=O. Mass spectrum: m/z (c.i.) 236 ([M+1]+
56%), 204 (100), 162 (63).
ethanol, m.p. 76–77 (lit.9 74–76 ).
1515m, 1223s, 1164s, 1037m, 685m cm
(KBr) 3035s, 1750s,
1H n.m.r. 1 12,
,
max
1
.
t, J 7 1 Hz, OCH2CH3; 1 39, d, J 7 2 Hz, CHCH3; 2 32,
s, ArCH3; 3 88–4 13, m, OCH2CH3, CHCH3; 7 09, d, J 7 9
Hz, H 30, H 50; 7 70, d, J 7 9 Hz, H 20, H 60; 8 05, br s, NH3.
13C n.m.r. 13 8, OCH2CH3; 15 7, CH(CH3)2; 21 3, ArCH3;
49 1, CH(CH3)2; 62 2, OCH2CH3; 125 9, C 20, C 60 or C 30,
C 50; 128 9, C 20, C 60 or C 30, C 50; 140 5, C 10 or C 40; 141 1,
C 10 or C 40; 169 8, C=O.
1-Methyl-3-phenyl-4,5-dihydro-1,2,4-triazin-6(1 H)-one (8)
Methylhydrazine (1 4 ml, 27 0 mmol) was added to a solu-
tion of the ethyl glycinate (5a) (3 98 g, 17 9 mmol) in isopropyl
alcohol (15 ml). After the solution was stirred at room temper-
ature overnight, the solvent and excess of methylhydrazine were
removed leaving a yellow solid which was puri ed by chromato-
graphy over silica gel. Elution with dichloromethane/methanol
mixtures (<5% methanol) gave a solid which was recrystallized
from ethyl acetate/cyclohexane to give the 1-methyl triazinone
(8) (747 mg, 22%). The melting point and spectroscopic data
were identical to those of an authentic sample.12 Further elu-
tion of the same column with increasing amounts of methanol
(>5%) gave a solid which was recrystallized from methanol
to a ord 2-methyl-3-phenyl-2,5-dihydro-1,2,4-triazin-6(1H )-one
(9) (2 38 g, 70%). The melting point and spectroscopic data
for this compound were identical to those of an authentic
sample.12 Most of the 2-methyl isomer (9) in the crude product
can be easily isolated by trituration of the crude product with
dichloromethane, in which it is insoluble.
The p-Toluenesulfonic Acid Salt (1f) of Ethyl 2-Amino-2-
methylpropanoate
A mixture of 2-amino-2-methylpropanoic acid (25 00 g,
242 mmol) and ethyl p-toluenesulfonate (53 4 g, 266 mmol)
was suspended in anhydrous ethanol (400 ml) and heated under
re ux for 36 h. Evaporation under reduced pressure gave a
white solid which was suspended in anhydrous diethyl ether
(200 ml) and ltered to give the salt (1f) as a white solid (73 2
g, 99%). A sample was recrystallized from ethanol/diethyl
ether to a ord a white solid, m.p. 121–123 .
2990s, 1744s, 1544m, 1190s, 815s, 766w, 681s, 570s cm
n.m.r. 1 21, t, J 7 1 Hz, OCH2CH3; 1 52, s, C(CH3)2;
(KBr)
.
max
1
1H
2 35, s, ArCH3; 4 15, q, J 7 1 Hz, OCH2CH3; 7 15, d, J
8 3 Hz, H 30, H 50; 7 75, d, J 8 3 Hz, H 20, H 60; 8 28, br
1,2-Dimethyl-3-phenyl-2,5-dihydro-1,2,4-triazin-
6(1 H)-one (7)
s, +NH3CH2. 13C n.m.r.
13 8, OCH2CH3; 21 3, ArCH3;
23 5, C(CH3)2; 57 2, C(CH3)2; 62 4, OCH2CH3; 126 0, C 20,
C 60 or C 30, C 50; 128 8, C 20, C 60 or C 30, C 50; 140 3, C 10
or C 40; 141 6, C 10 or C 40; 171 5, C=O.
(i) Reaction of (5a) with 1,2-dimethylhydrazine. A solu-
tion of the ethyl glycinate (5a) (752 mg, 3 40 mmol) and
1,2-dimethylhydrazine (409 mg, 6 80 mmol) (prepared by neu-
tralization of the dihydrochloride salt with sodium methoxide)
in dry methanol (5 ml) was heated in a sealed Claris tube at 130
for 2 h. The mixture was cooled, the solvent was evaporated
under reduced pressure, and the residue was chromatographed
over silica gel. Elution with dichloromethane/methanol mix-
tures a orded the 1,2-dimethyl compound (7) (240 mg, 34%).
G.l.c. Rt 14 8 min, 100%; m.p. 88–89 (Found: C, 64 7; H,
6 5; N, 20 4%; [M+1]+ , 204 113. C11H13N3O requires C,
Ethyl N-[Methoxy(phenyl)methylidene]glycinate (5a)12
Ethyl glycinate hydrochloride (1a) (1 63 g, 11 7 mmol) was
added to a solution of methyl benzimidate hydrochloride (2)
(2 00 g, 11 7 mmol) in dichloromethane (20 ml). Triethyl-
amine (reagent grade, 1 62 ml, 11 7 mmol) was added and
the solution was stirred at room temperature overnight. The
mixture was adsorbed on a short column of silica gel which
was eluted with dichloromethane. Concentration of the eluate
gave (5a) (1 55 g, 60%) as a colourless oil. G.l.c. Rt 12 36
65 0; H, 6 5; N, 20 7%; [M+1]+ , 204 114).
3056m, 2985w, 1670s, 1578w, 1449w, 1421w, 1266s, 781m,
( lm)
max
1
739s, 706m cm
.
234 nm (log 4 16). 1H n.m.r.
min, 97%.
1373m, 1282s, 1190s cm
( lm) 2984m, 2946m, 1746s, 1672s, 1435m,
1
max
max
.
1H n.m.r. 1 20, t, J 7 1 Hz,
2 91, s, N(1)CH3 or N(2)CH3; 3 20, s, N(1)CH3 or N(2)CH3;
4 20, s, CH2; 7 27–7 50, m, 3H, Ar; 7 67–7 82, m, 2H, Ar.
13C n.m.r. 32 3, N(1)CH3 or N(2)CH3; 39 2, N(1)CH3 or
N(2)CH3; 50 5, CH2; 128 6, C 20, C 60 or C 30, C 50; 128 9,
C 20, C 60 or C 30, C 50; 131 6, C 40; 132 5, C 10; 160 7, C=N
or C=O; 166 4, C=N or C=O. Mass spectrum: m/z (c.i.) 204
([M+1]+ , 100%), 122 (6), 100 (2).
(ii) Methylation of the 2-methyl compound (9). A solu-
tion of 2-methyl-3-phenyl-2,5-dihydro-1,2,4-triazin-6(1H )-one
(9) (860 mg, 4 55 mmol) in anhydrous methanol (20 ml) was
added dropwise with stirring to a freshly prepared solution of
sodium methoxide (270 mg, 5 mmol) in anhydrous methanol
OCH2CH3; 3 85, s, OCH3; 4 05, s, NCH2; 4 13, q, J 7 1 Hz,
OCH2CH3; 7 25–7 39, m, Ar. 13C n.m.r. 14 1, OCH2CH3;
52 1, NCH2; 53 5, OCH3; 60 7, OCH2CH3; 127 8, C 20, C 60
or C 30, C 50; 128 5, C 20, C 60 or C 30, C 50; 129 8, C 40; 131 6,
C 10; 164 6, C=N; 171 2, C=O. Mass spectrum: m/z (c.i.)
222 ([M+1]+ , 100%), 190 (70), 155 (3), 148 (22), 135 (6),
118 (4), 104 (2), 86 (3).
Ethyl (RS)-N-[Methoxy(phenyl)methylidene]alaninate (5b)
The p-toluenesulfonic acid salt (1e) of ethyl (RS)-alaninate
(6 70 g, 22 2 mmol) was added to a solution of methyl benzim-
Although the p-toluenesulfonic acid salt (1f) of ethyl 2-amino-2-methylpropanoate has been reported in two papers,8,9 no
spectroscopic data or physical properties have been reported other than its rate constant of saponi cation.

384
D. J. Collins, T. C. Hughes and W. M. Johnson
(10 ml) under argon. Freshly distilled methyl iodide (290 l,
4 55 mmol) was then added and the mixture was stirred at room
temperature for 2 days. The mixture was evaporated to dryness
and the residue was triturated with ethyl acetate (3 30 ml).
Evaporation of the ltrate and recrystallization of the residue
from ethyl acetate/light petroleum a orded the 1,2-dimethyl
triazinone (7) (595 mg, 64%) as a white solid, identical (m.p.
and spectroscopic data) with the material described above.
extract was washed with saturated sodium chloride solution
(50 ml), dried and evaporated under reduced pressure to give
the 2-benzamido ester (6c) as a white solid (14 0 g, 100%).
A sample recrystallized from toluene had m.p. 119 0–119 5
(lit.17 121 0–121 5 ). G.l.c. Rt 13 239 min, 100%. G.l.c.m.s.
Rt 17 409 min, 100%; mass spectrum: m/z (e.i.) 235 (M+
1%), 190 (1), 163 (4), 162 (33), 146 (1), 121 (1), 105 (100), 77
(35), 51 (11). (KBr) 3255s, 3065m, 2995m, 1737s, 1631s,
1547s, 1466m, 1386m, 1333m, 1272m cm
,
max
1
.
1H n.m.r. 1 23,
1,4-Dimethyl-3-phenyl-4,5-dihydro-1,2,4-triazin-
6(1 H)-one (12)
t, J 7 1 Hz, OCH2CH3; 1 64, s, C(CH3)2; 4 19, q, J 7 1 Hz,
OCH2CH3; 6 98, br s, NH; 7 32–7 49, m, 3H, Ar; 7 73–7 79,
m, 2H, Ar. 13C n.m.r.
14 1, OCH2CH3; 24 6, C(CH3)2;
Ethyl sarcosinate hydrochloride (11) (496 mg, 3 23 mmol)
was added to a suspension of N -methylbenzohydrazonoyl bro-
mide hydrobromide (10) (950 mg, 3 23 mmol) in anhydrous
dichloromethane (50 ml) and anhydrous methanol (20 ml).
The suspension was cooled to 0 and a solution of anhydrous
triethylamine (2 69 ml, 19 4 mmol) in anhydrous methanol
(30 ml) was added dropwise with stirring while the tempera-
ture was maintained at 0 . The mixture was allowed to warm
slowly to room temperature while it was stirred overnight
and then evaporated in vacuum. The residue was dissolved
in dichloromethane (75 ml) and washed with water (30 ml).
The aqueous layer was extracted with dichloromethane (25 ml)
and the combined extract was washed with saturated sodium
chloride solution, dried and concentrated to a ord a yellow
solid. Chromatography of the solid over silica gel and elution
with dichloromethane/methanol a orded the 1,4-dimethyl tri-
azinone (12) (478 mg, 73%), m.p. 130–131 . G.l.c. Rt 20 1
56 8, C(CH3)2; 61 5, OCH2CH3; 126 9, C 20, C 60 or C 30,
C 50; 128 4, C 20, C 60 or C 30, C 50; 131 4, C 40; 134 6, C 10;
166 6, NC=O; 174 8, OC=O. Mass spectrum: m/z (c.i.) 236
([M+1]+ , 100%), 218 (26), 162 (38), 130 (5), 115 (2), 105 (21).
Ethyl 2-([Chloro(phenyl)methylidene]amino)-2-methyl-
propanoate (21)
Phosphorus pentachloride (5 31 g, 25 5 mmol) was added
to ethyl 2-benzamido-2-methylpropanoate (6c) (6 00 g, 25 5
mmol) in anhydrous carbon tetrachloride (100 ml) under argon.
The mixture was heated under re ux for 2 h, cooled and ltered.
Evaporation of the ltrate under reduced pressure gave 6 32 g
of a colourless oil. The 1H n.m.r. spectrum showed it to contain
89% of the imidoyl chloride (21) and 11% of the benzamido
ester (6c). Compound (21) gave
1662m, 1596w, 1535w, 1491m, 1268s, 1146s, 878m, 745s cm
( lm) 2991m, 1735s,
1
max
.
min, 99% (Found: C, 64 6; H, 6 5; N, 20 9%; [M+1]+
204 113. 11H13N3O requires C, 65 0; H, 6 5; N, 20 7%;
[M+1]+ , 204 114).
(KBr) 2920w, 1660s, 1604s, 1468m,
1440m, 1392m, 1342m, 1221m, 808m, 760m, 733s, 706m cm
,
1H n.m.r. (CCl4/CDCl3) 1 28, t, J 7 1 Hz, OCH2CH3; 1 63,
s, C(CH3)2; 4 19, q, J 7 1 Hz, OCH2CH3; 7 31–7 47, m, Ar,
3H; 7 95–8 94, m, Ar, 2H. 13C n.m.r. (CCl4/CDCl3) 14 3,
OCH2CH3; 26 4, C(CH3)2; 60 9, OCH2CH3; 64 6, C(CH3)2;
128 1, C 20, C 60 or C 30, C 50; 129 1, C 20, C 60 or C 30, C 50;
131 5, C 40; 136 3, C 10; 140 8, C=N; 174 2, C=O. The crude
material was used directly in the next step.
C
max
1
.
1H n.m.r. 2 73, s, N(1)CH3 or N(4)CH3; 3 23, s, N(1)CH3
or N(4)CH3; 3 87, s, CH2; 7 37, s, Ar. 13C n.m.r. 35 6,
N(1)CH3 or N(4)CH3; 39 1, N(1)CH3 or N(4)CH3; 51 0, CH2;
128 9, C 20, C 30, C 50, C 60; 129 8, C 40; 132 2, C 10; 149 3,
C=N; 158 5, C=O. Mass spectrum: m/z (c.i.) 204 ([M+1]+
100%), 122 (52), 105 (23).
,
5,5-Dimethyl-3-phenyl-4,5-dihydro-1,2,4-triazin-
6(1 H)-one (20)
Hydrazine monohydrate (3 ml, 53 mmol) was added drop-
wise to a freshly prepared solution of the imidoyl chloride
(21) (3 3 g, 13 mmol) in anhydrous dichloromethane (100 ml)
cooled to 78 under argon. The mixture was allowed to
warm slowly to room temperature and stirred overnight. It
was then diluted with dichloromethane (100 ml), washed with
saturated sodium hydrogen carbonate solution (50 ml) and
saturated sodium chloride solution. The dried extract was
evaporated under reduced pressure to give a white solid which
was recrystallized from ethyl acetate/light petroleum to give
the 5,5-dimethyl triazinone (20) (2 46 g, 92%) as a white solid,
m.p. 223–225 . G.l.c. Rt 14 62 min, 100% (Found: C, 65 2;
H, 6 5; N, 20 9%; [M+1]+ , 204 113. C11H14N3O requires
Ethyl 2-Amino-2-methylpropanoate Hydrochloride (1c)
Thionyl chloride (20 9 ml, 360 mmol) was added dropwise to
anhydrous ethanol (135 ml) at 15 under an argon atmosphere.
2-Amino-2-methylpropanoic acid (30 g, 288 mmol) was then
added, the mixture was allowed to warm to room temperature
and heated under re ux for 1 h. Evaporation of the solvent
gave the ester hydrochloride (1c) (48 30 g, 100%) as a white
solid. A sample recrystallized from anhydrous ethanol had
m.p. 158 5–159 0 (lit.21 158–159 ).
2645m, 2582m, 2035w, 1745s, 1593m, 1522m, 1473m, 1366m,
(KBr) 2945s(br),
max
1
1309m, 1233m, 1188s cm
t, J 7 1 Hz, CH2CH3; 1 47, s, C(CH3)2; 4 16, q, J 7 1 Hz,
CH2CH3; 8 86, br s, NH3. 13C n.m.r.
((CD3)2SO) 13 7,
.
1H n.m.r. ((CD3)2SO) 1 20,
C, 65 0; H, 6 5; N, 20 7%; [M+1]+ , 204 114).
3197m(br), 3066m, 1664s, 1622s, 1407m, 989w, 775w, 692w
(KBr)
max
CH2CH3; 23 1, NC(CH3)2; 55 6, NC(CH3)2; 61 7, CH2CH3;
171 3, C=O.
1
cm
s, C(CH3)2; 6 39, br s, NH; 7 25–7 43, m, 3H, Ar; 7 63–7 75,
.
225 (log 4 21), 297 nm (3 92). 1H n.m.r. 1 41,
max
m, 2H, Ar; 9 58, br s, NH. 13C n.m.r.
25 0, CH3; 52 5,
Ethyl 2-Benzamido-2-methylpropanoate (6c)
C(CH3)2; 126 1, C 20, C 60 or C 30, C 50; 127 8, C 20, C 60 or
C 30, C 50; 129 5, C 40; 132 2, C 10; 146 0, C=N; 167 2, C=O.
Mass spectrum: m/z (c.i.) 204 ([M+1]+ , 100%), 188 (4), 176
(3).
Anhydrous triethylamine (20 8 ml, 150 mmol) was added
dropwise to a solution of ethyl 2-amino-2-methylpropanoate
hydrochloride (1c) (10 00 g, 60 mmol) in dichloromethane
(50 ml). A solution of benzoyl chloride (7 6 ml, 66 mmol)
in dichloromethane (20 ml) was added and the mixture was
stirred at room temperature for 1 h. Evaporation of the
mixture under reduced pressure gave a white solid which was
dissolved in diethyl ether (100 ml) and washed with saturated
sodium hydrogen carbonate solution (50 ml). The aqueous layer
was extracted with diethyl ether (75 ml) and the combined
3-Phenyl-4,5-dihydro-1,2,4-triazin-6(1 H)-one (15)
A solution of hydrazine monohydrate (1 0 ml, 20 mmol) in
anhydrous methanol (10 ml) was added dropwise with stirring
to a freshly prepared solution of the imidoyl chloride ester (14)12
(1 09 g, 4 8 mmol) in anhydrous diethyl ether (20 ml) at 78
Warning—addition of hydrazine to imidoyl chlorides was found to be highly exothermic.

Dihydro-1,2,4-triazin-6(1H )-ones. II
385
2
3
under argon. The mixture was then allowed to warm to room
temperature and stirred for 1 h. The solvents were evaporated
and a solution of the residue in ethyl acetate (200 ml) was washed
successively with saturated sodium hydrogen carbonate (75 ml)
and saturated sodium chloride solution (30 ml). Evaporation
of the dried extract gave a solid which was recrystallized from
ethyl acetate to a ord the 3-phenyl triazinone (15) (495 mg,
Camparini, A., Celli, A. M., Ponticelli, F., and Tedeschi,
P., J. Heterocycl. Chem., 1978, 15, 1271; Prokofeva, A. F.,
Sapozhnikova, Zh. S., Putsikina, E. B., Volkova, V. N.,
and Melnikov, N. N., Chem. Heterocycl. Compd. (Engl.
Transl.), 1993, 1048 (Chem. Abstr., 1993, 119, 49349k).
El-Abadelah, M. M., Hussein, A. Q., and Thaher, B. A.,
Heterocycles, 1991, 32, 1879.
Kjaer A., Acta Chem. Scand., 1953, 7, 1024.
Lerestif, J. M., Perrocheau, J., Tonnard, F., Bazureau, J.
P., and Hamelin, J., Tetrahedron, 1995, 51, 6757.
Schmidt, E., Ber. Dtsch. Chem. Ges., 1914, 47, 2545.
Cornforth, J. W., and Cornforth, R. H., J. Chem. Soc.,
1947, 96.
Ueda, K., Bull. Chem. Soc. Jpn, 1979, 52, 1879.
Yamamoto, T., Ueda, K., Ando, S., Aoyagi, H., and Izumiya,
N., Mem. Fac. Sci., Kyushu Univ., Ser. C, 1981, 13, 81
(Chem. Abstr., 1982, 96, 20436).
Reddy, K. V., Jin, S.-J., Arora, P. K., Sfeir, D. S., Maloney,
S. C. F., Urbach, F. L., and Sayre, L. M., J. Am. Chem.
Soc., 1990, 112, 2332.
Hunter, M. J., and Ludwig, M. L., J. Am. Chem. Soc.,
1962, 84, 3491; Perez, M. A., Dorado, C. A., and Soto, J.
L., Synthesis, 1983, 483.
Collins, D. J., Hughes, T. C., and Johnson, W. M., Aust.
J. Chem., 1996, 49, 463.
Shi, Y., Shi, N., Sun, X., Hu, H., Wu, M., and Yong,
Z., Bopuxue Zashi, 1989, 6, 306 (Chem. Abstr., 1990, 112,
234684j).
Collins, D. J., Hughes, T. C., Johnson, W. M., and Mackay,
M. F., Acta Crystallogr., Sect. C, 1996, 52, 2865.
Chaloupka, S., and Heimgartner, H., Chimia, 1978, 32, 332.
Ulrich, R., ‘Chemistry of Imidoyl Halides’ (Plenum: New
York 1968); Kantlehner, W., and Mergen, W. W., in ‘Com-
prehensive Organic Functional Group Transformations’ (Eds
A. R. Katritzky, O. Meth-Cohn and C. W. Rees) Vol. 5,
Ch. 5.17, p. 654 (Pergamon: Oxford 1995).
Obrecht, D., and Heimgartner, H., Helv. Chim. Acta, 1987,
70, 102.
Andersen, T. P., Ghattas, A.-B. A. G., and Lawesson,
S.-O., Tetrahedron, 1983, 39, 3419.
4
5
59%), m.p. 221–222 (lit.18 209–215 ).
3211m(br), 3059m, 2913w, 1657s, 1628s, 1573m, 1540m, 1419s
(KBr) 3371s,
max
1
cm
.
1H n.m.r.
((CD3)2SO) 3 82, s, CH2; 7 36, br s,
6
7
N(1)H; 7 37–7 46, m, 3H, Ar; 7 67–7 78, m, 2H, Ar; 10 44,
N(4)H. 13C n.m.r. ((CD3)2SO) 42 7, C 5; 125 7, C 20, C 60
or C 30, C 50; 128 2, C 20, C 60 or C 30, C 50; 129 6, C 40; 132 4,
C 10; 144 9, C 3; 161 0, C 6. Mass spectrum: m/z (c.i.) 176
([M+1]+ , 100%), 153 (3), 135 (15), 104 (10), 87 (3). A similar
reaction carried out at room temperature gave a lower yield
(16–18%) of the 3-phenyl triazinone (15); the major product
was 5-ethoxy-2-phenyloxazole (13), m.p. 35–36 (lit.22 38–39 ).
8
9
10
11
Methylation of 3-Phenyl-4,5-dihydro-1,2,4-triazin-
6(1 H)-one (15)
A solution of the 3-phenyl triazinone (15) (1 00 g, 5 7 mmol)
in anhydrous dimethylformamide (10 ml) was added dropwise
with stirring to an ice-cold suspension of sodium hydride
(171 mg, 80%, 5 7 mmol) in anhydrous dimethylformamide
(2 ml) under argon. The cooling bath was removed and the
mixture was stirred for 1 h, then it was then recooled to 0 and
a solution of freshly distilled methyl iodide (355 l, 5 7 mmol)
in anhydrous dimethylformamide (5 ml) was added dropwise.
The mixture was stirred for 2 h at 0 , and then evaporated
to dryness (eventually 25 /0 05 mmHg). The 1H and 13C
n.m.r. spectra and t.l.c. indicated that the crude product
contained the 1-methyl 3-phenyl triazinone (8) (93%) and the
3-phenyl triazinone (15) (7%). This mixture was dissolved
in water (30 ml) and extracted with ethyl acetate (3 50 ml).
The extract was washed with brine, dried and evaporated
under reduced pressure to give a yellow solid. Recrystallization
of this from ethyl acetate/light petroleum gave the 1-methyl
3-phenyl triazinone (8) (940 mg, 87%). This was identical
(m.p., 1H and 13C n.m.r. spectra) with the material prepared
previously.12 Compound (12) was prepared by repeating the
above methylation procedure on compound (8). Spectra for
compound (12) are reported above.
12
13
14
15
16
17
18
19
Grimmett, M. R., and Keene, B. R. T., Adv. Heterocycl.
Chem., 1988, 43, 127; Butler, R. N., and O’Shea, D. F., in
“Rodd’s Chemistry of Carbon Compounds” Vol. IV I/J,
Ch. 47, p. 251 (Elsevier: Amsterdam 1995).
Prokofeva, A. F., Sapozhnikova, Zh. Z., Volkova, V. N.,
Negrebetskii, V. V., Pokrovskaya, L. A., and Melnikov, N.
N., Chem. Heterocycl. Compd. (Engl. Transl.), 1991, 772
(Chem. Abstr., 1992, 117, 48504d).
Adkins, H., and Billica, H. R., J. Am. Chem. Soc., 1948,
70, 3121.
Huisgen, R., Sturm, H. J., and Binsch, G., Chem. Ber.,
1964, 97, 2864.
20
References
1
Sen, M., J. Indian Chem. Soc., 1929, 6, 1001; Ohta, T.,
21
22
and Kurosu, S., J. Pharm. Soc. Jpn, 1949, 69, 189 (Chem.
Abstr., 1950, 44, 1491); Badr, M. Z. A., Aly, M. M., Khalil,
Z. H., and Attalla, A. A., Indian J. Chem., Sect. B, 1982,
21, 115.