Regioselective alkylations of optically active 4,5-dihydro- 1,2,4- triazin-6(1H)-ones

Article abstract of DOI:10.1016/S0040-4039(99)02162-0

Regiocontrolled alkylations of chiral 4,5-dihydrotriazin-6-ones using sodium hydride in DMF are reported. By this approach different N l-alkyl, N1,N4-dialkyl and N4-alkyl dihydrotriazinones could be obtained in good yields with conservation of their optical activity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02162-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 671–674
Regioselective alkylations of optically active
4,5-dihydro-1,2,4-triazin-6(1H)-ones
Laurent Sanière, Martine Schmitt and Jean-Jacques Bourguignon ∗
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081 du CNRS, Faculté de Pharmacie,
74 route du Rhin, 67400 Illkirch, France
Received 15 September 1999; accepted 18 November 1999
Abstract
Regiocontrolled alkylations of chiral 4,5-dihydrotriazin-6-ones using sodium hydride in DMF are reported. By
this approach different N1-alkyl, N1,N4-dialkyl and N4-alkyl dihydrotriazinones could be obtained in good yields
with conservation of their optical activity. © 2000 Published by Elsevier Science Ltd. All rights reserved.
Among the different 1,2,4-triazinones described in the literature, only a few are 4,5-dihydro-1,2,4-
triazin-6-ones II.1,2 They constitute valuable heterocycles as scaffolds for combinatorial chemistry. For
this goal, an efficient control of different substituents within the heterocycle is needed to generate the
largest molecular diversity. Their preparation often involves reaction of an N-acyl α-amino acid derivative
I with hydrazine.2 In particular starting from either an N-alkyl N-acyl α-aminoester I,3 or an N-alkyl
hydrazine,4 it is formally possible to prepare, respectively, N4 or N1 substituted dihydrotriazinones
(Scheme 1). However, yields are generally poor, and the methods lead to significant racemisation. In
addition specific starting materials have to be available or synthesised for each selected dihydrotriazinone.
Scheme 1.
The work reported here describes an easy and versatile method of regioselective alkylation of
either the amide or the amidine moieties present in the structure of the corresponding N-unsubstituted
dihydrotriazinones. The optically pure (S)-5-methyl-3-phenyl-4,5-dihydrotriazin-6-one 1a, chosen as the
reference compound, was prepared according to literature procedures, starting from (L)-N-thiobenzoyl
alanine ethylester and hydrazine.2 When 1a was reacted with methyl iodide in THF degassed with a
∗
Corresponding author. E-mail: jjb@pharma.u-strasbg.fr (J.-J. Bourguignon)
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02162-0
tetl 16090

672
stream of nitrogen, in the presence of sodium hydride as a base, besides important amounts of starting
material (40%) and the expected N1-methyl derivative 2a (25%), two unexpected triazinones 3 and 4
were isolated from the reaction mixture (Scheme 2). They result from the dehydrogenation of the starting
dihydrotriazinone 1a facilitated in our experimental conditions.
Scheme 2. (i) MeI (1.2 equiv.), NaH (1.2 equiv.), THF, N2 atm., rt; (ii) MeI (1.2 equiv.), NaH (1.2 equiv.), DMF, N2 atm. 0°C
or rt
In order to increase the yield of alkylation and to avoid the formation of other side-products, the
procedure was reinvestigated. Several results could be summarised as follows:
(i) when starting from 1a in the presence of sodium hydride in THF degassed with a stream of nitrogen,
but in the absence of alkylating agent, dehydrogenation occurred and the corresponding triazinone
3 was obtained nearly quantitatively.5
(ii) temperature (rt or 0°C) did not strongly influence the reaction: a mixture of dihydrotriazinones 1a,
2a and unsubstituted triazinone 3 was recovered in similar ratios.
(iii) when the reaction was carried out in DMF, increasing amounts (55%) of N1-methyl derivative 2a
were obtained. Surprisingly in DMF, no dehydrogenation reaction took place at 0°C, or at room
temperature. As a result of the higher reactivity of nucleophilic substitution reactions performed in
DMF, a significant amount (10%) of N1,N4-dimethyl dihydrotriazinone 5a was also isolated from
the reaction mixture (Scheme 2).
(iv) replacement of sodium hydride by potassium tert-butoxide did not significantly modify the course
of the reaction, whereas in absence of base no reaction occurred, even with heating (80°C). As
expected the deprotonation is the key step for alkylation.
According to pathway ii (Scheme 2), several N1-alkyl 4,5-dihydrotriazin-6-ones were prepared6,7
using various alkyl halides (Scheme 3, entries 1–5).
Moreover, further alkylation reactions could be performed on the amidine moiety of N1-
substituted dihydrotriazinones 2 using the same experimental conditions as above (a second alkyl
halide/NaH/DMF/0°C). The corresponding N1,N4-dialkyl derivatives were prepared7 in good yields
(Scheme 3, entries 6–9).
This approach may constitute an efficient way for introducing various substituents on N4-position
in a regioselective manner. Indeed the removal of the N1-substituent of N1,N4-dialkyl compounds 5
would lead to derivatives 6 substituted only on N4-position (Scheme 4). The N1-benzyl group of 5c
was not a satisfactory protective group, as it could not be removed by catalytic hydrogenation using
various catalysts. In addition, debenzylation using aluminium trichloride in toluene8 gave only low yields.
However, the benzyloxymethyl group was found to be an advantageous protective group of N1-nitrogen:

673
Scheme 3.
alkylation yields were similar to N1-benzyl derivatives but cleavage of benzyloxymethyl group of 5e
using boron tribromide led to the N4-substituted 4,5-dihydrotriazin-6-one 6 in good yields (70%).
Scheme 4. (i) AlCl3, toluene, 60°C, 24 h, 35%; (ii) BBr3, CH2Cl2, rt, 1 h, 70%
As part of the validation of our synthetic approach to build libraries of novel heterocycles, it
was important to check whether racemisation occurred during the different alkylation steps perfor-
med in basic medium (presence of a strong base in DMF). As a model of the novel substituted
1
dihydrotriazinones, the optical purity of 2a was determined by H NMR using europium tris-[3-
(heptafluoropropylhydroxymethylene-(+)-camphorate] as the chiral lanthanide shift reagent (LSR)9. The
efficacy of the method was first tested with a mixture of racemates ((R,S)-2a). After addition of Eu(hfc)3
([Eu(hfc)3]/[substrate]=0.5), the signals of the N1-methyl group (s, 3.39 ppm) and C5-methyl group (d,
1.48 ppm, J=7 Hz) were fully resolved into two diastereomeric singlets (6.38 and 6.48 ppm) and two
diastereomeric doublets (3.76 and 3.88 ppm, J=9 Hz), respectively. No trace of such splitting signals
were found for (S)-2a prepared in our conditions, even at higher concentrations of Eu(hfc)3. In a similar
manner, the synthesised (S)-6 was found optically pure by the LSR method. These results strongly support
that in our experimental alkylation conditions, no racemisation occurred.
In conclusion, we have described here an easy and general method of preparation of mono (N1 or
N4) and dialkyl (N1 and N4) chiral 4,5-dihydrotriazin-6-ones with control of regioselectivity (N1 versus
N4) and retention of optical activity. These works involved alanine for building substituted triazinones,

674
but could be extended to other α-aminoacids (Phe, see Scheme 3, entries 2 and 6) and therefore will be
useful to prepare original libraries of peptidomimetics.10
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6. Preparation of 2a: 150 mg (0.8 mmol) of 1a in dry DMF (5 ml), under nitrogen atmosphere was cooled at 0°C. Methyl
iodide (135 mg, 0.95 mmol) and a dispersion of sodium hydride in mineral oil (w/w 60%, 38 mg, 0.95 mmol) were added
successively to the mixture, which was kept at 10°C for 4 h. The mixture was diluted with 50 ml of water, extracted with
ethyl acetate. The organic layer was evaporated in vacuo, and the residue was chromatographed on silica gel (hexane:ethyl
1
acetate, 1:1) to provide 90 mg (55%) of a white solid, mp 108–110°C. H NMR (300 MHz): 1.49 (d, 3H, JCH–CH3 =7 Hz,
CH-CH3), 3.39 (s, 3H, N-CH3), 4.21 (qd, 1H, JCH–CH =7 Hz, JCH–NH=1 Hz, -CH), 5.10–5.20 (m, 1H, NH), 7.40–7.50 (m, 3H,
3
H arom), 7.60–7.75 (m, 2H, H arom).
7. Authentic samples of 2c and 5c were also prepared by unambiguous synthetic methods, as introduced previously,3,4 and
compared with our reaction products in order to ascertain the structure of different regioisomers.
8. Kaji, K.; Kusuya, M. Chem. Pharm. Bull. 1970, 18, 147–156.
9. El-Abdelah, M. M.; Hussein, A. Q.; Thaher, B. A. Heterocycles 1991, 32, 1879–1895.
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