Immediate deamination from the aminomethyl group attached to 1,2-dihydropyrazin-2-one derivative during catalytic hydrogenation

Article abstract of DOI:10.1016/S0040-4039(02)01944-5

The catalytic hydrogenation of 3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one to remove benzyloxycarbonyl (Z) groups resulted in a side reaction. Purification by reverse-phase HPLC and analysis by proton nuclear magnetic resonance

Full text of DOI:10.1016/S0040-4039(02)01944-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8137–8139
Immediate deamination from the aminomethyl group attached to
1,2-dihydropyrazin-2-one derivative during catalytic
hydrogenation
Yoshio Okada,a,b,* Yutaka Fujisawa,a Akihisa Morishita,a Kimitaka Shiotani,a Anna Miyazaki,a
Yoshio Fujita,a Tingyou Li,b Yuko Tsuda,a,b Toshio Yokoi,a,b Sharon D. Bryantc and
Lawrence H. Lazarusc
aFaculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan
bHigh Technology Research Center, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan
cPeptide Neurochemistry, LCBRA, National Institute of Environmental Health Science, Research Triangle Park, NC 27709, USA
Received 28 June 2002; revised 2 September 2002; accepted 6 September 2002
Abstract—The catalytic hydrogenation of 3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one to remove
benzyloxycarbonyl (Z) groups resulted in a side reaction. Purification by reverse-phase HPLC and analysis by proton nuclear
magnetic resonance (1H NMR) spectroscopy identified the product as 3-aminomethyl-5,6-dimethyl-1,2-dihydropyrazin-2-one. It
was determined through the synthesis of two 1,2-dihydropyrazin-2-one derivatives, composed of alanine and 2,3-diaminopropionic
acid that deamination occurred specifically and easily (under atmospheric pressure and at the room temperature) only in the case
of 6-benzyloxycarbonylaminomethyl-3,5-dimethyl-1,2-dihydropyrazin-2-one. The catalytic hydrogenation of 3,6-bis(benzyloxycar-
bonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one specifically yields the deaminated product, 3-aminomethyl-5,6-dimethyl-
1,2-dihydropyrazin-2-one. © 2002 Elsevier Science Ltd. All rights reserved.
The opioid mimetic, 3,6-bis(4%-tyrosylaminobutyl)-5-
methyl-1,2-dihydropyrazin-2-one exhibited moderate
binding activity to m-opioid receptors.1 In order to
synthesize more potent and selective m-opioid agonists
and to study structure–activity relationships, additional
MALDI-TOF mass spectrometry (MS) was utilized to
investigate the side reaction that occurred during the
hydrogenation step in the removal of the Z groups.
Compounds (I–IV) were hydrogenated and the prod-
ucts were analyzed by MS as a function of time (10, 20,
30, 60 min). Hydrogenation of compounds I–III yielded
the desired synthetic product (Ia–IIIa) within 10 min-
utes and deprotection was completed within 60 min-
utes. In contrast, the reaction for compound IV yielded
both the desired (IVa) and unexpected products (V)
within the first 10 minutes and after 60 minutes all of
compound IV was transformed into the unexpected
product (V), which had the molecular weight of 153.
Z-protected
1,2-dihydropyrazin-2-one
derivatives
(Scheme 1; I–IV) were prepared to be used as synthetic
intermediates.
Four 1,2-dihydropyrazin-2-one derivatives (I–IV) con-
taining one to four methylene linkers were prepared
(Scheme 1).1–3 The Boc group of the protected dipep-
tidyl chloromethyl ketone was removed with HCl-diox-
ane, and the resulting peptidyl chloromethyl ketone
hydrochloride salt was refluxed in either acetonitrile or
methanol to form the 1,2-dihydropyrazin-2-one ring.
The Z-protected derivative was hydrogenated over a Pd
catalyst in 50% acetic acid to remove the Z groups.
Although hydrogenation of three derivatives (I–III)
gave the corresponding desired products (Ia–IIIa),
hydrogenation of compound IV produced an unex-
pected product (V) instead of IVa during the final step.
This new and unexpected product (V) was purified by
reverse-phase HPLC and identified by proton nuclear
magnetic resonance (1H NMR) spectroscopy in pyri-
dine-d5. The desired product was anticipated to contain
two aminomethyl groups and one methyl group,
whereas NMR results indicated that the product had
one aminomethyl group and two methyl groups [l ppm
(400MHz): 4.87 (2H, s, methylene of aminomethyl
group), 2.23 (3H, s, methyl), 2.15 (3H, s, methyl)]. In
addition, the molecular weight of the unexpected
product (153) was smaller than that of the desired
* Corresponding author. E-mail: okada@pharm.kobegakuin.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01944-5

8138
Y. Okada et al. / Tetrahedron Letters 43 (2002) 8137–8139
a function of time (10, 20, 30 min, and 1, 2, 4 and 6 h).
Both deprotected products VIII and IX obtained during
hydrogenation should have the same molecular weight,
153.20; however, the deaminated form (X) which had a
molecular weight of 138.17, was detected at 20 min and
the entire compound IX was transformed after 6 h
reaction time.
product (IVa) (168). The presence of only one
aminomethyl group could be explained by deamination
of the aminomethyl moiety attached to the 1,2-dihy-
dropyrazin-2-one ring at either position 3 or 6.
To determine from which position the amino group was
removed, two 1,2-dihydropyrazin-2-one derivatives,
composed of alanine and 2,3-diaminopropionic acid,
were prepared (Scheme 2).
Purification by reverse-phase HPLC and 1H NMR
analysis of compound VIII in pyridine-d5 revealed that
the catalytic hydrogenation of compound VI produced
3-aminomethyl-5,6-dimethyl-1,2-dihydropyrazin-2-one
Compounds VI and VII were hydrogenated as stated
above, and the reaction mixture was analyzed by MS as
[l: ppm 4.87 (2H, s, 3-CH
6
2NH2); 2.22 (3H, s, 5- or
)]. Similar analyses of
6-CH3); 2.15 (3H, s, 5- or 6-CH3
6
6
compound X revealed that catalytic hydrogenation of
compound VII yielded 3,5,6-trimethyl-1,2-dihydropy-
razin-2-one; the deaminated product [l: ppm 2.60, 2.24,
2.15 (3H×3, s, 3- or 5- or 6-CH6 3)].
These data confirm that deamination occurred specifi-
cally at position 6 of the 1,2-dihydropyrazin-2-one ring
only in the case of compound VII. In addition, it
demonstrated that catalytic hydrogenation of com-
pound IV specifically gave the deaminated product,
3-aminomethyl-5,6-dimethyl-2(1H)-1,2-dihydropyrazin-
2-one. Furthermore, the time of deamination was
shorter for compound IV (60 min) relative to com-
pound VII (6 h). The dissimilar reaction kinetics may
have resulted from the different partial electron densi-
ties or differences in the dimensional structure of the
starting material (Schemes 1 and 2).
Interestingly, our group reported previously that cata-
lytic hydrogenation of the compounds 6-benzyl-3-benz-
yloxycarbonylmethyl - 5 - methy - 1,2 - dihydropyrazin - 2-
one (A) and 3-benzyl-6-benzyloxycarbonylmethyl-5-
methyl-1,2-dihydropyrazin-2-one (B) specifically pro-
duced the decarboxylated 6-benzyl-3,5-dimethyl-
1,2-dihydropyrazin-2-one due to low electron density of
methylene moiety at position 3 on the 1,2-dihydropy-
razin-2-one ring.4 Decarboxylation was specifically
observed at position 3 on the 1,2-dihydropyrazin-2-one
ring. These differences allowed us to presume that
deamination and decarboxylation were caused by dif-
ferent mechanisms. Deamination would occur owing to
the location of an amino group at a similar position to
benzyl or allyl,5–10 rather than owing to low electron
density. It can be deduced that the property of CꢀN
bond at position 6 is similar to that of a benzylic or
allylic CꢀN bond, while the property of the CꢀN bond
at position 3 is quite different from that of benzylic or
allylic CꢀN bond.
Scheme 1. Reagents and conditions: (i) HCl–dioxane; (ii)
reflux in either methanol or acetonitrile; (iii) H2/Pd in 50%
acetic acid.
It is interesting that deamination of an aminomethyl
moiety attached to 6 position of 1,2-dihydropyrazin-2-
one derivative occurred easily at room temperature
under atmospheric pressure, although reactivity of
deamination from benzylamine derivatives are very
low.5,6,11 This high reactivity in the present report might
be attributable to the low electron density of CꢀN bond
compared with benzyl-amine or relatively high affinity
of 1,2-dihydropyrazin-2-one moiety for the palladium
Scheme 2. Reagents and conditions: (i) HCl–dioxane; (ii)
reflux in methanol; (iii) H2/Pd, 50% acetic acid.

Y. Okada et al. / Tetrahedron Letters 43 (2002) 8137–8139
8139
catalyst. We suggested that 1,2-dihydropyrazin-2-one
6-methyl-group can be a candidate for novel benzyl
type amino protecting group removable by catalytic
hydrogenolysis at ordinary temperature and pressure.
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5. Velluz, L.; Amiard, G.; Heyness, R. Bull. Soc. Chim. Fr.
Acknowledgements
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This work was supported in part by a Grant-in-Aid for
Kobe Gakuin University Joint Research (B).
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