observed in these experiments appears to be consistent with
previous reports with pyruvaldehyde.10
step could lead to the formation of bis-hydrazone species
9c,14 which subsequently undergoes a nonselective cycliza-
tion.
As various R,R-dibromoketones can be conveniently
prepared by bromination of the corresponding methyl
ketones,11 we investigated the reactivity of these compounds
as masked keto aldehyde equivalents. In this regard, treatment
of dibromopinacolone 7 with aminoguanidine bicarbonate
(AGB) in the presence of KOAc in MeOH at 67 °C gave a
2:1 (8a:8b) mixture of aminotriazines12 in 35% assay yield
(Scheme 3). Addition of a catalytic amount of nBuN4I did
We reasoned that to drive the formation of hydrazone 9a,
which would lead to the desired aminotriazine, the difference
in reactivity between the two electrophilic sites should be
more pronounced. In this regard, the possibility of converting
the dibromide group to the more reactive iminium species
10 was investigated. However, treatment of 7 with morpho-
line (4.1 equiv) in THF at 67 °C for 48 h only afforded a
5:1 mixture of keto aminal 11 and mono-morpholinated
ketone 12 (Scheme 4).15 Formation of the reduced product
Scheme 3
Scheme 4
1216 could be minimized (e10 mol %) if the reaction was
carried out at lower temperature (45-50 °C) and longer time
(96 h). Similar results were obtained with N,N-dimethylamine
(2 M solution in THF) or N-methylpiperazine.
Despite no detected formation of the iminium species 10,
the keto aminal 11 was isolated and subsequently subjected
to condensation with AGB in refluxing MeOH or THF.
Under these reaction conditions, a 2:1 mixture of amino-
triazines (8a:8b) was obtained after 24 h in 54% assay yield
(Table 1). An improved ratio of 7:1 (8a:8b) was observed
when aminoguanidine hydrochloride (AG-HCl) was used
instead. On the basis of these latter results, we further
investigated the regioselectivity of the reaction under slightly
more acidic conditions, where in situ formation of the more
not appear to change the reaction outcome. A possible
explanation for the observed reaction outcome is an initial
indiscriminate attack by the hydrazine nitrogen to give a
mixture of two hydrazone intermediates (Scheme 3, 9a,b),13
which after the requisite CdN bond isomerization and
cyclization yields the regioisomeric mixture of amino-
triazines. On the other hand, a slow cyclization in the final
(3) Sanfilippo, P. J.; Urbanski, M.; Press: J. B.; Dubinsky, B.; Moore,
J. B., Jr. J. Med. Chem. 1988, 31, 2221 and references therein.
(4) Spitzer, W. A.; Victor, F.; Don Pollock, G.; Hayes, J. S. J. Med.
Chem. 1988, 31, 1590 and references therein.
(5) The parent 3-amino-1,2,4-triazine and 3-amino-5,6-dimethyl-1,2,4-
triazine were prepared by condensation between aminoguanidine and glyoxal
and 2,3-butadione, respectively, see: Erickson, J. G. J. Am. Chem. Soc.
1952, 74, 4706. Other preparations of aminotriazines include but are not
limited to the folowing: (a) Ring amination of the corresponding halo-
triazines with KNH2 in liquid ammonia (29-54% yield), see: (1) Rykowski,
A.; van der Plas, H. C. J. Org. Chem. 1980, 45, 881. (2) Rykowski, A.;
van der Plas, H. C. J. Heterocycl. Chem. 1982, 19, 653. (b) MnO2 oxidation
of the corresponding 4-substituted-1,2-diaminoimidazoles (6-26% yield),
see: Nakajima, M.; Hisada, R.; Anselme, J.-P. J. Org. Chem. 1978, 43,
2693. For additional methods, see refs 2.
(6) Phenyl glyoxal and pyruvaldehyde are both commercially available
as hydrates. Other keto aldehydes can be accessed by oxidation of the
corresponding methyl ketones, see for example: (a) Bruce, M. J.; McLean,
G. A.; Royles, B. J. L.; Smith, D. M.; Standring, P. N. J. Chem. Soc., Perkin
Trans. I 1995, 14, 1789. (b) Desmond, R.; Mills, S.; Volante, R. P.; Shinkai,
I.; Desmond, R. A.; Mills, S.; Volante, R. P.; Shinkai, I. Synth. Commun.
1989, 19, 379. (c) Floyd, M. B.; Du, M. T.; Fabio, P. F.; Jacob, L. A.;
Johnson, B. D. J. Org. Chem. 1985, 50, 5022. (d) Uchida, K.; Masuda, G.;
Aoi, Y.; Nakayama, K.; Irie, M. Chem. Lett. 1999, 10, 1071. (e) Pfueller,
O. C.; Sauer, J. Tetrahedron Lett. 1998, 39, 8821. (f) Gleiter, R.; Krennrich,
G. Angew. Chem., Int. Ed. Engl. 1986, 25, 449.
(9) The assay was run with an Agilent 1100 HPLC instrument and YMC-
Pack Pro 18C column (250 × 4.6 mm i.d.) under the following conditions:
80% MeCN:20% 0.1% v H3PO4/H2O mobile phase, 1 mL/min flow rate,
UV detector (210 nm wavelength), and 35 °C column temperature.
(10) (a) Merck & Co., Inc.: British Patent 755,036, 1956; Chem. Abstr.
1957, 51, 8151. (b) Saikawa, I.; Maeda, T. Yakugaku Zasshi 1967, 87, 1501.
(c) Suzuki, T.; Okazaki, M.; Mitsuhashi, K. J. Heterocycl. Chem. 1986,
23, 935.
(11) (a) Bromine: Nan’ya, S.; Ishida, H.; Moiji, E. J.; Butsugan, Y.;
Bajji, A. C. J. Heterocycl. Chem. 1994, 31, 401. (b) Boeykens, M.; De
Kimpe, N. Tetrahedron 1994, 50, 12349. (c) PhMe3NBr3: Jacques, J.;
Marquet, A. Org. Synth. 1988, 175.
(12) For a previous preparation of 8a, see: Rykowski, A.; van der Plas,
H. C. J. Heterocycl. Chem. 1982, 19, 653.
(13) Only hydrazone 9a was identifiable by 1H NMR during the reaction.
(14) Condensation of 14 with AG-HCl in THF:H2O (1:1) at 67 °C for
24 h afforded a similar bis-hydrazone species, which upon addition of K2CO3
or KOAc cyclized to give a 1.5:1 mixture of the aminotriazines (8a:8b).
(15) For conversion of various dibromides to the corresponding aminals,
see: (a) Kerfanto, M.; Brault, A.; Venien, F.; Morvan, J. M.; Le Rouzic,
A. Bull. Chem. Soc. Fr. 1975, 196. (b) Morvan, J. M.; Kerfanto, M.; Brault,
A. Bull. Chem. Soc. Fr. 1975, 1679.
(7) Aminoguanidine is commercially available as a hydrochloride or
bicarbonate salt. The relatively inexpensive bicarbonate was extensively
used in our studies and it was converted to the more soluble acetate salt by
treatment with 1 equiv of AcOH.
(8) In all cases, the regioisomeric ratio during the aminotriazine formation
was calculated by using 1H NMR integration values of the sp2 C-H of the
triazine ring (see Supporting Information).
(16) For a previously observed reduction capability of a secondary amine
during a halide displacement reaction, see: Howk, B. W.; McElvain, S.
M. J. Am. Chem. Soc. 1932, 54, 282.
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Org. Lett., Vol. 5, No. 13, 2003