N-(alkyl)-2-amino-1,4-pyrazine derivatives: Synthesis and antioxidative properties of 3- and 3,5-p-hydroxyphenyl-substituted compounds

Article abstract of DOI:10.1055/s-2003-37652

2-Amino-5-(p-hydroxyphenyl)-1,4-pyrazine and 2-amino-3,5-bis(p-hydroxyphenyl)-1,4-pyrazine are endowed with excellent antioxidative properties. For a possible development in medicinal chemistry, the lipophilicity of these lead compounds has to be increased. Therefore various methods of N-alkylation were systematically explored. The best results were obtained by quenching aminopyrazinyl anion with alkyl iodides, and by coupling aldehydes (reductive amination) in the presence of phenylsilane and tin catalyst. Aminopyrazines equipped with linear alkyl side-chains of at least six carbons showed improved radical-scavenging properties in lipidic media.

Full text of DOI:10.1055/s-2003-37652

PAPER
513
N-(Alkyl)-2-amino-1,4-pyrazine Derivatives: Synthesis and Antioxidative
Properties of 3- and 3,5-p-Hydroxyphenyl-Substituted Compounds
N
-(Alkyl)-2-am
a
ino-1,4-py
u
razine Deriv
l
atives: 3- and
J
3,5-
p
-H
y
e
droxyphen
a
yl-Substitu
n
ted Compou
j
Cécile Marchand,b Roland Touillaux,c Jean-François Rees,b Jacqueline Marchand-Brynaert*a
a
Unité de Chimie Organique et Médicinale, Université Catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur 1,
1348 Louvain-la-Neuve, Belgium
Fax +(32)10474168; E-mail: marchand@chim.ucl.ac.be
b
Unité de Biologie Animale, Université Catholique de Louvain, Bâtiment Carnoy, Place Croix du Sud 4, 1348 Louvain-la-Neuve, Belgium
c
Unité de Chimie Structurale, Université Catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur 1, 1348 Louvain-la-Neuve,
Belgium
Received 25 November 2002
has been conducted. Nucleophilic substitution of chloro-
and bromopyrazines with amines was reported to give low
yields.7 On the other hand, aminopyrazine could be alky-
lated with 1-hydroxymethylbenzotriazole, a very strong
Abstract: 2-Amino-5-(p-hydroxyphenyl)-1,4-pyrazine and 2-ami-
no-3,5-bis(p-hydroxyphenyl)-1,4-pyrazine are endowed with excel-
lent antioxidative properties. For a possible development in
medicinal chemistry, the lipophilicity of these lead compounds has
to be increased. Therefore various methods of N-alkylation were electrophile in acidic medium.8 Lastly, condensation reac-
systematically explored. The best results were obtained by quench-
tion of aminopyrazine with glyoxals has been investigated
to prepare bicyclic compounds.9
ing aminopyrazinyl anion with alkyl iodides, and by coupling alde-
hydes (reductive amination) in the presence of phenylsilane and tin
We considered four strategies which possibly could meet
our objective, namely: (i) nucleophilic substitution of
chloropyrazine (method A); (ii) reductive amination of al-
dehydes with aminopyrazine (method B), optionally in-
cluding isolation of the Schiff base intermediate (method
B′); (iii) acylation of aminopyrazine followed by reduc-
tion of the amide intermediate (method C); and (iv) alky-
lation of the aminopyrazine anion (method D, Scheme1).
The unsubstituted heterocycles (model compounds) chlo-
ropyrazine 1 and aminopyrazine 2, are commercially
available. The precursors required to prepare antioxidant
compounds, i.e. O-protected 3- and 3,5-p-hydroxyphenyl-
2-amino-1,4-pyrazines 5–8 (Scheme 2) were obtained by
selective bromination of 2 followed by Pd-mediated
cross-coupling to arylboronic acids (Suzuki reaction).
catalyst.
Aminopyrazines equipped with linear alkyl side-chains of at least
six carbons showed improved radical-scavenging properties in lip-
idic media.
Key words: pyrazines, alkylations, heterocycles, amines, reduc-
tions, antioxidants
Coelenteramine (2-amino-3-benzyl-5-p-hydroxyphenyl-
1,4-pyrazine) is one of the major metabolites of the oxida-
tive degradation of coelenterazine,1 a bioluminescence
substrate for several marine organisms. The main structur-
al feature of this compound is the unique combination of
phenol and aminopyrazine moieties, leading to excellent
antioxidant properties.2 Recently, we disclosed the inter-
est of phenol-substituted aminopyrazines as new lead
compounds in medicinal chemistry,3 since numerous
pathological conditions result from an oxidative stress
(e.g. ischemia-reperfusion injury, atherosclerosis, inflam-
matory diseases, cancers, and ageing).4 In continuation of
our studies, we are now interested in the development of
more lipophilic compounds for an optimal bioavailability.
This article summarizes our efforts in the synthesis of 2-
alkylamino-1,4-pyrazine derivatives and their evaluation
as in vitro inhibitors of lipid peroxidation.
2a,b
Compounds 5 and 7 have been previously described,
while t-butyldimethylsilyloxyphenyl derivatives 6 and 8
are new compounds, similarly prepared from t-butyldi-
methylsilyloxyphenylboronic acid 4 (see experimental).
The choice of these precursors relies upon the ease with
which phenol deprotection could be realised on the final
alkylation product.
We first confirmed that chloropyrazine 1 is poorly reac-
tive in nucleophilic substitution with primary amines
(method A, Table 1, entries 1–2). Indeed, reaction of 1
with benzylamine or butylamine in the presence of potas-
sium fluoride (3 equiv) in refluxing acetonitrile (5 d) led
to the desired compounds 3a and 3c in low yields (respec-
tively, 14 and 16%). Therefore, alkylaminopyrazine de-
rivatives should be prepared from the corresponding
aminopyrazines. A recent literature report10 showed the
possibility to perform the direct reductive amination of al-
dehydes with electron-deficient anilines using phenylsi-
lane as stoichiometric reductant and catalysis by
dibutyltin dichloride. In our hands, this procedure was
found to be also suitable for the one-step alkylation of
The synthesis of secondary amines is well documented in
the aliphatic series. But as far as the aromatic chemistry is
concerned, the traditional methods appear much less ef-
fective,5 particularly in the heterocyclic series. The prob-
lem
has
recently
been
addressed
for
2-
(alkylamino)pyridine derivatives.6 In the case of 2-(alkyl-
amino)pyrazines, to our knowledge, no systematic study
Synthesis 2003, No. 4, Print: 18 03 2003.
Art Id.1437-210X,E;2003,0,04,0513,0522,ftx,en;P06502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

514
P. Jeanjot et al.
PAPER
N-alkyl derivatives 15a–d, but in poor yields (Figure 1,
Table 1, entries 14 to 17). However, under prolonged re-
action times (>14 d) or heating, it was possible to signifi-
cantly increase the yields as illustrated with the
preparation of compounds 15d and 14g/15g from 6
(Table 1, entries 17–19), and 21a from 3,5-bis(p-tert-bu-
tyldimethylsilyloxyphenyl)-2-amino-1,4-pyrazine
(Figure 1, Table 1, entry 20).
(8)
Scheme 1
aminopyrazine 2 (method B, Table 1, entries 3–7); mod-
erate to good yields of N-alkylamino-1,4-pyrazines 3a–
d,g were collected by reacting 2 with respectively benzal-
dehyde, phenylacetaldehyde, butyraldehyde, isobutyral-
dehyde and dodecylaldehyde (THF, 20 °C, 1–7 d).
Similarly, the reaction of 5-(p-tert-butyldimethylsilylox-
yphenyl)-2-amino-1,4-pyrazine (6) with aldehydes, fol-
lowed by in situ deprotection of the phenol moiety
(compounds 14) by tetrabutylammonium fluoride, led to
Figure 1
Scheme 2
Synthesis 2003, No. 4, 513–522 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
N-(Alkyl)-2-amino-1,4-pyrazine Derivatives: 3- and 3,5-p-Hydroxyphenyl-Substituted Compounds
Table 1 Synthesis of 1,4-Pyrazine Derivatives
515
Then, we turned to the alternative strategy, method C,
(acylation/reduction) and tested the method with benzoyl
chloride. Reaction of 5-(p-methoxyphenyl)-2-amino-1,4-
pyrazine (5) with benzoyl chloride and triethylamine
(CH2Cl2, reflux, 2 d) produced the bis-acylation product
10 in 21% yield after purification; unreacted 5 was recov-
ered, together with traces of 9 (R′ = Me) (Figure 1,
Table 1, entry 9). Treatment of aminopyrazine 6 with an
excess of benzoyl chloride (5 equiv) in pyridine (60 °C, 1
day) gave a 1:5 mixture of mono-acylation (9) and bis-
acylation products; 9 could be isolated by chromatogra-
phy in about 10% yield (Figure 1, Table 1, entry 8). A bet-
ter recovery of mono-acylated product 9 (i.e. 48%) could
be obtained by treating 6 first with a strong base (LiH-
MDS in THF), then with benzoyl chloride. Starting from
3,5-bis(p-methoxyphenyl)-2-amino-1,4-pyrazine (7), we
similarly obtained a 1:2 mixture of mono- (11) and bis-
acylation (12) products (PhCOCl, 5 equiv, pyridine,
60 °C, 17 h) which were separated by chromatography in
17 and 34% yields (Figure 1, Table 1, entry 10). LiAlH4
reduction (THF, reflux) of amide 11 furnished the second-
ary amine 19a in good yield. However, the corresponding
tertiary amine 22a (Figure 1) was not formed by reduction
of imide 12; we obtained a mixture of 11, 19a and 7.
Entry
Compd
(Figure 1)
R
Methoda
Yield (%)
1
2
3a
3c
Ph
A
14
C3H7
Ph
A
16
3
3a
B
72
4
3b
CH2Ph
C3H7
CHMe2
C11H23
Ph
B
50
5
3c
B
63
6
3d
B
70
7
3g
B
56
8
9
C
10b–48
21c
17/34
25
9
10
Ph
C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
11/12
13a
13a
15a
15a
15b
15c
15d
14g
15g
21a
14e/17e
15f
Ph
C
Ph
B′
Ph
D
48
Ph
E
95
Ph
B + F
B + F
B + F
B + F
B
17
CH2Ph
C3H7
CHMe2
C11H23
C11H23
Ph
10
We further tried to prepare Schiff bases by condensing 5
and 7 with benzaldehyde in refluxing toluene containing
p-toluenesulfonic acid as catalyst (Scheme 1, Method B′).
The resulting intractable mixtures (Schiff bases and oligo-
mers, from 1H NMR analysis) were directly reduced with
NaBH4 (i-PrOH, 40 °C, 17 h) to furnish the N-benzyl de-
rivatives 13a and 19a in 25 and 37% yields, respectively
(Figure 1, Table 1, entries 11 and 26).
25
41d
55d
57d
78
F
B + F
D
Lastly, we examined the direct alkylation strategy of ami-
nopyrazines with alkyl halides under basic conditions
(Scheme 1, method D). We were aware of problems that
could be encountered, such as N-N′-bis-alkylation and re-
action at the endocyclic N atom, as usually pointed out for
the heterocyclic amines.11 Moreover, depending on the
base strength, elimination from alkyl halides could occur.
Reaction of 5 with large excesses (20 equiv) of benzylbro-
mide and triethylamine in ethanol (reflux, 3 d) gave only
21% of N-benzyl derivative 13a. This is due to the very
low nucleophilicity of 5, an electron-deficient heterocy-
clic amine. Thus, we decided to generate in situ the ami-
nopyrazinyl anion, before the alkyl halide was added.
LiHMDS or BuLi in THF or DME were readily used for
C5H11
C9H19
C13H27
C5H11
C5H11
Ph
45/40
55
D + F
D + F
F
15h
15e
18e
19a
19a
21a
20e/23e
20f
50
72
F
69
B′
37
Ph
D
60
Ph
E
79
C5H11
C9H19
C13H27
C5H11
C9H19
C5H11
D
48/20
63 (crude)e
30
D
this
purpose
(pKa
of
2-aminopyrazine
in
DMSO = 25.812). Thus, N-benzyl derivatives 13a and 19a
were prepared, in 48 and 60% yield respectively
(Figure 1, Table 1, entries 12 and 27), by treatment of pre-
cursors 5 and 7 with LiHMDS in THF (0 °C, 2 h) followed
by reaction with benzyl bromide (20 °C, THF, 1 d); the
products were separated from starting materials and N,N′-
dibenzyl derivatives (16a and 22a) by chromatography.
The derivatization of 6 and 8 with alkyl chains (hexyl, de-
cyl and tetradecyl) required an optimised procedure as fol-
lows: (i) deprotonation with BuLi (1.2–1.3 equiv) in
DME, in the presence of tetramethylethylenediamine (1
21h
21e
21f
D + F
F
65
F
61
24e
F
63
a Synthetic methods A, B, C and D: see Scheme 1; deprotection meth-
ods: E = EtSH–AlCl3; F = Bu4N+F–
b First intermediate of method C; dibenzoyl product also formed.
c First intermediate of method C; monobenzoyl product also formed.
d Prolonged reaction time or reflux
e Product not isolated
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516
P. Jeanjot et al.
PAPER
equiv) at 0 °C for 2 h; (ii) alkylation with alkyl halide (5 N-alkyl derivatives 15 and 21 were more active at concen-
equiv) in DME at 45 °C for 3–4 days. The use of alkyl io- trations of 2.5 to 0.1 µM. But the N,N′-bis-alkylderiva-
dides allowed to significantly improve the yields, compar- tives 18e and 24e did not show an additional increase of
atively to alkyl bromides and alkyl tosylates. But the activity. Our compounds are more potent than EGCG
formation of N,N′-dialkyl compounds could not be avoid- (epigallocatechin gallate)14a considered as a good refer-
ed. In the case of substitution with hexyl iodide, the mono ence in the domain. Thus, the enhanced lipophilicity of
and bis-alkylated products 14e/17e (Figure 1, Table 1, en- the N-substituted compounds was a favourable factor, but
try 21) and 20e/23e (entry 29) were separated by chroma- no clear correlation could be found with physicochemical
tography. Otherwise, the mono-alkylated compounds measurements such as log k′IAM and log Poctanol/water
(14f,h, 20f,h) were not isolated before the final deprotec- (Table 2). Apparently, linear side chains with at least six
tion of the silyl ethers (Table 1, entries 22, 23, 28 and 31). carbon atoms are adequate to provide an excellent antiox-
idant activity to our phenolic aminopyrazine derivatives,
Unmasking the phenol substituents from methyl ether pre-
in a test mimicking cell-membrane protection towards ox-
cursors was realized as previously described2a,b by treat-
idative stress damages. Such compounds could be readily
ment with ethanethiol and aluminium trichloride (Table 1,
prepared by direct alkylation of aminopyrazinyl anions
entries 13 and 28). The tert-butyldimethylsilyl ethers were
with alkyl iodides (method D), or by reductive amination
cleaved as usual with tetrabutylammonium fluoride13
of aldehydes in a one-step process using phenylsilane and
(Table 1, entries 14–17, 19–20, 22–25 and 31–34). All
dibutyltin dichloride catalysis (Method B). This last meth-
compounds were fully characterized by NMR (1H and
od would be preferred, since chromatographic purifica-
13C) and mass spectroscopies (see experimental).
tions were easier due to the absence of bis-alkylated side
The radical-scavenging property of phenol-substituted
aminopyrazines was evaluated by their capacity to inhibit
the propagation rate of lipid peroxidation induced with
AAPH.14 Compared to the N-unsubstituted reference
compounds 25 and 262a (Table 2), all the corresponding
products. The family of N-alkyl aminopyrazines we have
investigated constitutes
a new type of phenolic
antioxidants15 with promising developments in medicinal
chemistry. A theorical study is actually in progress with a
view to quantify the effect of the aminopyrazinyl moieties
Table 2 Physicochemical Properties of 1,4-Pyrazine Derivatives
b
Cpd
15a
15b
15c
15d
15e
15f
R1
R2
R3
R4
H
log k′IAM
log Poctanol/water
> 2
2.5 µM%a
59.9 (3.6)
79.7 (10.2)
73.4 (12.7)
67.6 (10.7)
93.1 (7.3)
90.4 (10.1)
87.0 (16)
92.2 (6.6)
90.1 (10)
78.6 (2.2)
96.6 (9.5)
96.1 (12)
97.0 (8)
0.5 µM%a
39.1 (2.8)
41.9 (0.3)
31.9 (1.3)
25.0 (2.3)
74.5 (9.1)
70.2 (8.5)
/
0.1 µM%a
9.3 (7.1)
12.8 (4.5)
6.5 (5.2)
3.6 (3.3)
27.3 (3.3)
24.5 (6.1)
/
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
H
CH2Ph
(CH2)2Ph
C4H9
H
H
H
H
H
CH2i-Pr
C6H13
C10H21
C12H21
C14H29
C6H13
CH2Ph
C6H13
C10H21
C14H29
C6H13
H
H
H
H
1.91 (0.06)
H
H
15g
15h
18e
21a
21e
21f
H
H
H
H
4.35 (0.06)
2.79 (0.06)
74.9 (10.1)
75.6 (7.2)
/
21.4 (7.1)
10.4 (6.2)
/
H
C6H13
H
PhOH
PhOH
PhOH
PhOH
PhOH
H
> 2
H
78.5 (9.2)
80.2 (8.2)
78.3 (10.1)
87.3 (9.1)
25.0 (10)
69.4 (10)
14.4 (4.3)
21.8 (2.6)
15.2 (6.7)
21.7 (7.4)
29.6 (2.9)
4.1 (7.7)
18.9 (6.2)
/
H
21h
24e
25
H
C6H13
H
96.5 (10)
33.3 (7.9)
82.4 (6.1)
98.2 (4.5)
0.24 (0.06)
1.29 (0.06)
0.13 (0.01)
1.95 (0.09)
26
PhOH
H
H
EGCGc
a Percentage of inhibition of linoleate peroxidation initiated with AAPH.
b Capacity factor determined by HPLC on immobilized artificial membrane (IAM) column.
c From green tea.
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N-(Alkyl)-2-amino-1,4-pyrazine Derivatives: 3- and 3,5-p-Hydroxyphenyl-Substituted Compounds
517
Yield: 754 mg (2.50 mmol, 72%); Rf 0.26 (cyclohexane–EtOAc,
5:3); mp 120–122 °C.
1H NMR (300 MHz, CDCl3): δ = 0.23 [s, 6 H, Si(CH3)2], 0.98 [s, 9
H, C(CH3)3], 4.56 (s, 2 H, NH2), 6.90 (d, 2 H, J = 8.7 Hz, Harom),
7.72 (d, 2 H, J = 8.7 Hz, Harom), 8.03 (d, 2 H, J = 1.8 Hz, H3), 8.38
(d, 2 H, J = 1.8 Hz, H6).
13C NMR (75 MHz, CDCl3): δ = –4.5 (2 CH3Si), 18.2 [C(CH3)3],
25.6 (3 CH3), 120.5 (CHarom), 126.8 (CHarom), 129.9 (Carom), 131.6
(C3), 138 (C6), 142.8 (C5), 152.4 (C2), 156.1 (COSi).
on the phenolic O–H bond dissociation enthalpy, the sta-
bilisation of phenoxyl radical,16 and the Hartree–Fock in-
stability of the neutral molecules.17
Solvents were dried prior to use. Reagents (Aldrich or Acros) were
used as purchased. Mps (uncorrected) were determined on an Elec-
trothermal apparatus. 1H (200 MHz or 300 MHz) and 13C (50 MHz
or 75 MHz) NMR spectra were recorded on Varian Gemini 200 and
300 spectrometers. 1H (500 MHz) and 13C (125 MHz) NMR spectra
were recorded on a Bruker AM-500 spectrometer. Chemical shifts
are reported as δ values downfield from TMS. The mass spectra
(FAB, APCI or EI (70 eV) modes) were obtained on a Finnigan
MAT TSQ-70 instrument. TLC was carried out using silica gel 60
MS (FAB+): m/z = 302.3 (M + 1), 301 (M), 244 (M – C4H9).
Anal. Calcd for C16H23N3OSi 0.1 H2O (303.26): C, 63.36; H, 7.73;
N, 13.85. Found: C, 63.17; H, 7.52; N, 13.97.
F
254 plates (0.2 mm, Merck) and the spots were visualized using UV
3,5-Bis(p-tert-butyldimethylsilyloxyphenyl)-2-amino-1,4-pyra-
zine (8)
light (254 nm). Column chromatography was performed on Merck
silica gel 60 (70–230 mesh). Elemental analyses were obtained at
the University College London (UK).
A mixture of bis(benzonitrile)palladium (II) dichloride (445 mg,
1.16 mmol, 0.096 equiv) and 1,4-bis(diphenylphosphino)butane
(dppb) (597 mg, 1.40 mmol, 0.115 equiv) in anhyd toluene (15 mL)
was stirred at 20 °C, under argon atmosphere for 30 min, until a
creamy orange slurry of [1,4-bis(diphenylphosphino)butane]palla-
dium (II) chloride was formed. Then, 2-amino-3,5-dibromo-1,4-
pyrazine (3.1 g, 12.15 mmol, 1 equiv), p-tert-butyldimethylsilyl-
oxyphenyl boronic acid (4) (9 g, 35.6 mmol, 2.9 equiv), EtOH
(13 mL), aq Na2CO3 (1 M; 12.15 mL, 1 equiv) and toluene (50 mL)
were added to the preformed catalyst. The mixture was refluxed for
24 h under stirring. After cooling, H2O (70 mL) and EtOAc (70 mL)
were added. The aqueous phase was separated and extracted with
EtOAc (2 × 70 mL). The combined organic phases were washed
with brine (120 mL), dried (MgSO4), filtered over Celite, and con-
centrated in vacuo. Purification of the crude product was achieved
by flash chromatography (silica gel; EtOAc–cyclohexane, 1:5).
p-tert-Butyldimethylsilyloxyphenyl Boronic Acid (4)
To a cold solution (0 °C) of 4-bromophenol (10.56 g, 60.45 mmol)
and imidazole (6.29 g, 92.4 mmol) in anhyd CH2Cl2 (50 mL), was
added slowly tert-butyldimethylsilyl chloride (12.57 g, 81.73
mmol). The mixture was stirred 1 h at r.t., washed with brine (50
mL), dried (MgSO4), filtered and concentrated in vacuo. The crude
product (yellow oil) was dissolved in anhyd THF (75 mL) and
cooled at –78 °C under Ar atmosphere. BuLi (1.6 M in hexane, 41.5
mL, 66.5 mmol) was added dropwise and the reaction mixture was
stirred for an additional 15 min. Triisopropylborate (36 mL, 156
mmol) was added dropwise at –78 °C, the reaction mixture was
slowly warmed to r.t. and stirred overnight. Aq HCl (1 N) was add-
ed until the aqueous layer became acidic. The organic layer was
washed with brine (70 mL), dried (MgSO4), filtered and concentrat-
ed in vacuo. The yellow solid was washed with cold cyclohexane
and hot H2O.
Yield: 2.78 g (5.47 mmol, 45%); yellow solid; Rf 0.1 (cyclohexane–
EtOAc, 11:1); mp 123–125 °C.
1H NMR (500 MHz, CDCl3): δ = 0.21 [s, 6 H, Si(CH3)2], 0.24 [s, 6
H, Si(CH3)2], 0.99 [s, 9 H, C(CH3)3], 1.01 [s, 9 H, C(CH3)3], 4.73 (s,
2 H, NH2), 6.90 (d, 2 H, J = 8,6 Hz, Harom), 6.96 (d, 2 H, J = 8,6 Hz,
Harom), 7.70 (d, 2 H, J = 8.6 Hz, Harom), 7.83 (d, 2 H, J = 8,6 Hz,
Yield: 12.96 g (51.4 mmol, 85% yield); white solid; mp 205–
207 °C.
1H NMR (200 MHz, CDCl3): δ = 0.25 [s, 6 H, Si(CH3)2], 1.00 [s, 9
H, C(CH3)3], 6.97 (d, 2 H, J = 8.6 Hz, Harom), 8.13 (d, 2 H, J = 8.6
Hz, Harom).
13C NMR (50 MHz, CDCl3): δ = –4.3 (2 CH3Si), 18.3 [C(CH3)3],
25.7 (3 CH3), 119.8 (2 CHarom), 135.2 [CB(OH)2], 137.5 (2 CHarom),
159.8 (COSi).
H
arom), 8.34 (s, 1 H, H6).
13C NMR (125 MHz, CDCl3): δ = –4.5 (2 CH3Si), –4.4 (2 CH3Si),
18.1 [C(CH3)3], 18.2 [C(CH3)3], 25.6 (3 CH3), 25.6 (3 CH3), 120.3
(CHarom), 120.4 (CHarom), 126.9 (CHarom), 129.6 (CHarom), 130.4 (2
Carom), 136.6 (C6), 139.4 (C3), 142.9 (C5), 150.3 (C2), 155.9 (COSi),
Anal. Calcd for C12H21BO3Si (252.19): C, 57.15; H, 8.39. Found: C,
57.70; H, 8.16.
156.4 (COSi).
MS (APCI): m/z = 508.6 (M + 1) (C28H41N3O2Si2).
5-(p-tert-Butyldimethylsilyloxyphenyl)-2-amino-1,4-pyrazine
(6)
N-Alkylation, Method B; General Procedure
Aminopyrazine derivative (1 equiv) and dibutyltin dichloride (0.02
equiv) were added to a solution of the corresponding aldehyde (1.2
equiv) in anhyd THF (3 mL/mmol). The mixture was stirred 5 min,
then phenylsilane (1.1 equiv) was added dropwise and the solution
was allowed to stir at 20 °C for 24 to 300 h. H2O (4 mL/mmol) and
EtOAc (4 mL/mmol) were added. The aqeous phase was separated
and extracted with EtOAc (2 × 4 mL/mmol). The combined organic
phases were washed with brine (5 mL/mmol), dried (MgSO4), fil-
tered and concentrated in vacuo. The crude product was purified by
flash chromatography (silica gel; EtOAc–cyclohexane).
A mixture of bis(benzonitrile)palladium (II) dichloride (68 mg,
0.172 mmol, 0.05 equiv) and 1,4-bis(diphenylphosphino)butane
(dppb) (92 mg, 0.207 mmol, 0.06 equiv) in anhyd toluene (15 mL)
was stirred at 20 °C, under argon atmosphere for 30 min, until a
creamy orange slurry of [1,4-bis(diphenylphosphino)butane]palla-
dium (II) chloride was formed. Then, 2-amino-5-bromo-1,4-pyra-
zine (602 mg, 3.46 mmol,
1 equiv), p-tert-butyldimethyl-
silyloxyphenyl boronic acid (4) (1.06 g, 4.22 mmol, 1.2 equiv),
EtOH (1.43 mL), aq Na2CO3 (1 M; 3.5 mL, 1 equiv) and toluene (20
mL) were added to the preformed catalyst. The mixture was re-
fluxed for 24 h under stirring. After cooling, H2O (50 mL) and
EtOAc (50 mL) were added. The aqueous phase was separated and
extracted with EtOAc (2 × 50 mL). The combined organic phases
were washed with brine (100 mL), dried (MgSO4), filtered over
Celite, and concentrated in vacuo. Purification of the crude product
was achieved by flash chromatography (silica gel; EtOAc–cyclo-
hexane, 4:5).
N-Alkylation: Method D; General Procedure
A solution of BuLi (1.6 M in hexane, 1.2 to 1.3 equiv) was added
dropwise to a cold solution (0 °C) of aminopyrazine derivative (1
equiv) in DME (6 mL/mmol) and TMEDA (1 equiv); the mixture
was stirred 2 h. Then, iodoalkyl compound (5 equiv) was added and
the solution was allowed to stir at 45 °C for 3 to 5 days. EtOAc (10
mL/mmol) and Na2CO3 (1 M, 10 mL/mmol) were added. The aq
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518
P. Jeanjot et al.
PAPER
phase was separated and extracted with EtOAc (2 × 10 mL/mmol).
The combined organic phases were washed with brine (15 mL/
mmol), dried (MgSO4), filtered and concentrated in vacuo. The
crude product was purified by flash chromatography (silica gel;
EtOAc–cyclohexane).
MS (EI): m/z (%) = 151 (M, 34), 108 (M–C3H7, 100), 94.9 [M–
CH2CH(CH3)2, 25].
Anal. Calcd for C8H13N3 0.3 H2O (156.4): C, 61.34; H, 8.77; N,
26.84. Found: C, 61.29; H, 8.68; N, 26.82.
N-Isobutyl-2-amino-1,4-pyrazine (3d)
Yellow oil; Rf 0.28 (cyclohexane–EtOAc, 5:4).
Methyl Ether Deprotection; General Procedure
The protected compound was added to a stirred solution of AlCl3 or
AlBr3 (4 equiv/ether function) in ethanethiol (5–10 mL/mmol),
cooled at 0 °C (ice–H2O bath). The mixture was stirred for 18 h at
20 °C, then poured into H2O, acidified with aq HCl (1 N) and ex-
tracted with EtOAc (3 × 5–10 mL/mmol). The combined organic
layers were washed with brine and aq Na2CO3 (5%; 5 mL/mmol),
dried (MgSO4) and concentrated in vacuo. The crude product was
purified by flash chromatography (silica gel; EtOAc–cyclohexane).
1H NMR (300 MHz, CDCl3): δ = 0.98 (d, 6 H, J = 6.9 Hz, 2 CH3),
1.86–1.95 [m, 1 H, CH2CH(CH3)2], 3.17 (td, 2 H, J = 5.7, 1.2 Hz,
NHCH2), 4.85 (br s, 1 H, NH), 7.77 (d, 1 H, J = 2.4 Hz, H6), 7.88
(d, 1 H, J = 1.2 Hz, H3), 7.96 (dd, 1 H, J = 2.4, 1.2 Hz, H5).
13C NMR (75 MHz, CDCl3): δ = 20.4 (2 CH3), 28.4 [CH(CH3)2],
49.2 (NHCH2), 131.8 (C3), 132.4 (C5), 141.8 (C6), 154.9 (C2).
MS (EI): m/z (%) = 151 (M, 37) (C8H13N3), 108.0 [M – CH(CH3)2,
100], 94.9 [M – CH2CH(CH3)2, 26).
Silyl Ether Deprotection; General Procedure
To a cold (0 °C) solution of protected compound (1 equiv) in THF
(5 mL/mmol) was added dropwise a solution Bu4NF (1 M THF, 5%
H2O, 3 equiv), the mixture was stirred for 1 to 4 h at r.t., and con-
centrated in vacuo. H2O (4 mL/mmol) and EtOAc (4 mL/mmol)
were added. The aq phase was separated and extracted with EtOAc
(2 × 4 mL/mmol). The combined organic phases were washed with
brine (7 mL/mmol), dried (MgSO4), filtered and concentrated in
vacuo. The crude product was purified by flash chromatography
(silica gel; EtOAc–cyclohexane).
N-Dodecanyl-2-amino-1,4-pyrazine (3g)
Yellow solid; Rf 0.25 (cyclohexane–EtOAc, 5:2); mp 67–69 °C.
1H NMR (300 MHz, CDCl3): δ = 0.87 (t, 3 H, J = 7.3 Hz, CH3),
1.20–1.35 (m, 16 H, 8 CH2), 1.36–1.40 (m, 2 H, CH2), 1.60–1.64
(m, 2 H, CH2), 3.29–3.33 (m, 2 H, CH2), 4.63 (br s, 1 H, NH), 7.76
(d, 1 H, J = 2.8 Hz, H6), 7.86 (d, 1 H, J = 1.4 Hz, H3), 7.95 (dd, 1
H, J = 2.8, 1.4 Hz, H5).
13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 22.5 (CH2), 26.9
(CH2), 29.1 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (2 CH2), 29.5 (2
CH2), 31.8 (CH2), 41.5 (CH2NHAr), 131.6 (C3), 132.4 (C5), 141.8
(C6), 154.6 (C2).
N-Benzyl-2-amino-1,4-pyrazine (3a)
Yellow solid; Rf 0.28 (cyclohexane–EtOAc, 5:4); mp 69–71 °C.
1H NMR (300 MHz, CDCl3): δ = 4.56 (d, 2 H, J = 5.7 Hz, CH2),
5.00 (br s, 1 H, NHBn), 7.26–7.36 (m, 5 H, Harom), 7.82 (d, 1 H,
J = 2.7 Hz, H6), 7.88 (d, 1 H, J = 1.5 Hz, H3), 7.99 (dd, 1 H, J = 2.7,
1.5 Hz, H5).
13C NMR (75 MHz, CDCl3): δ = 45.7 (NHCH2Ph), 127.6 (3
CHarom), 128.8 (2 CHarom), 132.1 (C3), 133.2 (C5), 138.5 (Carom),
142.0 (C6), 154.4 (C2).
MS (APCI): m/z = 264.5 (M + 1) (C16H28N3).
N-Benzoyl-5-(p-tert-butyldimethylsilyloxyphenyl)-2-amino-1,4-
pyrazine (9)
White solid; Rf 0.37 (cyclohexane–EtOAc, 5:1); mp 157–158 °C.
1H NMR (300 MHz, CDCl3): δ = 0.24 (s, 6 H, 2 CH3Si), 1.0 [s, 9 H,
SiC(CH3)3], 6.95 (d, 2 H, J = 8.7 Hz, Harom), 7.45–7.65 (m, 3 H,
Harom), 7.86 (d, 2 H, J = 8.7 Hz, Harom), 7.95 (d, 2 H, J = 8.4 Hz,
MS (EI): m/z (%) = 185 (M, 100), 108 (M – Ph, 31).
Harom), 8.59 (d, 1 H, J = 1.5 Hz, H3), 8.64 (s, 1 H, NH), 9.71 (d, 1 H,
J = 1.5 Hz, H6).
Anal. Calcd for C11H11N3: C, 71.33; H, 5.99; N, 22.68. Found: C,
71.07; H, 6.14; N, 22.58.
MS (APCI): m/z = 406.4 (M + 1).
N-Phenethyl-2-amino-1,4-pyrazine (3b)
Yellow oil; Rf 0.27 (cyclohexane–EtOAc, 5:4).
Anal. Calcd for C23H27N3O2Si 0.1 H2O (422.88): C, 67.81; H, 6.74;
N, 10.32. Found: C, 67.80; H, 6.55; N, 9.98.
1H NMR (300 MHz, CDCl3): δ = 2.94 (t, 2 H, J = 6.9 Hz,
CH2CH2Ph), 3.63 (dd, 2 H, J = 6.9 Hz, 5.7 Hz, NHCH2), 4.61 (br s,
1 H, NHBn), 7.20–7.34 (m, 5 H, Harom), 7.79 (d, 1 H, J = 2.4 Hz,
H6), 7.83 (d, 1 H, J = 1.2 Hz, H3), 7.98 (dd, 1 H, J = 2.4, 1.2 Hz,
H5).
13C NMR (75 MHz, CDCl3): δ = 35.6 (CH2CH2Ph), 42.7
(NHCH2CH2), 126.7 (CHarom), 128.8 (2 CHarom), 128.9 (2 CHarom),
132.2 (C3), 132.9 (C5), 138.9 (CCH2CH2), 142.0 (C6), 154.5 (C2).
N,N′-Bis(benzoyl)-5-(p-methoxyphenyl)-2-amino-1,4-pyrazine
(10)
Yellow solid; Rf 0.54 (cyclohexane–EtOAc, 5:3); mp 151–152 °C.
1H NMR (300 MHz, CDCl3): δ = 3.85 (s, 3 H, CH3), 7.00 (d, 2 H,
J = 9.0 Hz, Harom), 7.37 (dt, 4 H, J = 7.2, 1.4 Hz, Harom), 7.48 (dt, 2
H, J = 7.6, 1.3 Hz, Harom), 7.79 (dd, 4 H, J = 7.1, 1.4 Hz, Harom),
7.93 (d, 2 H, J = 9.0 Hz, Harom), 8.58 (d, 1 H, J = 1.4 Hz, H3), 8.72
(d, 1 H, J = 1.4 Hz, H6).
13C NMR (75 MHz, CDCl3): δ = 55.6 (CH3O), 114.7 (2 CHarom),
128.5 (4 CHarom), 129.0 (2 CHarom), 129.6 (4 CHarom + Carom), 133.1
(2 CHarom), 134.3 (2 Carom), 139.8 (C3), 142.4 (C6), 148.3 (C5), 150.3
(C2), 161.5 (COCH3), 172.9 (2 C=O).
MS (EI): m/z (%) = 199 (M, 15), 108 (M–CH2Ph, 100).
Anal. Calcd for C12H13N3 0.3 H2O (204.4): C, 70.42; H, 6.71; N,
20.54. Found: C, 70.67; H, 6.63; N, 20.61.
N-Butyl-2-amino-1,4-pyrazine (3c)
MS (EI): m/z (%) = 409 (M, 100) (C25H19N3O3).
Yellow oil; Rf 0.29 (cyclohexane–EtOAc, 5:4).
1H NMR (300 MHz, CDCl3): δ = 0.96 (t, 3 H, J = 7.8 Hz, CH3),
1.39–1.47 (m, 2 H, CH2), 1.57–1.67 (m, 2 H, CH2), 3.30–3.37 (m, 2
H, NHCH2), 4.80 (br s, 1 H, NH), 7.78 (d, 1 H, J = 2.4 Hz, H6), 7.88
(d, 1 H, J = 1.2 Hz, H3), 7.95 (dd, 1 H, J = 2.4, 1.2 Hz, H5).
13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 20.3 (CH2CH3), 31.7
(NHCH2CH2), 41.4 (NHCH2CH2), 131.8 (C3), 132.4 (C5), 142.0
(C6), 154.8 (C2).
N-Benzyl-5-(p-methoxyphenyl)-2-amino-1,4-pyrazine (13a)
Yellow solid; Rf 0.47 (cyclohexane–EtOAc, 5:3); mp 153 °C.
1H NMR (300 MHz, CDCl3): δ = 3.83 (s, 3 H, OCH3), 4.57 (d, 2 H,
J = 5.6 Hz, NHCH2Ph), 5.09 (s, 1 H, NHBn), 6.95 (d, 2 H, J = 8.7
Hz, Harom), 7.32 (m, 5 H, Harom), 7.78 (d, 2 H, J = 9.0 Hz, Harom),
7.92 (d, 1 H, J = 1.3 Hz, H3), 8.39 (d, 1 H, J = 1.3 Hz, H6).
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N-(Alkyl)-2-amino-1,4-pyrazine Derivatives: 3- and 3,5-p-Hydroxyphenyl-Substituted Compounds
519
13C NMR (75 MHz, CDCl3): δ = 46.0 (NHCH2Ph), 55.5 (OCH3),
114.4 (2 CHarom), 126.9 (2 CHarom), 127.7 (3 CHarom), 128.9 (2
CHarom), 130.1 (Carom), 130.9 (C3), 138.2 (Carom), 138.6 (C6), 141.9
(C5), 152.9 (C2), 159.8 (COCH3).
N-Dodecanyl-5-(p-tert-butyldimethylsilyloxyphenyl)-2-amino-
1,4-pyrazine (14g)
Yellow solid; Rf 0.88 (cyclohexane–EtOAc, 1:1); mp 65–66 °C.
1H NMR (200 MHz, CDCl3): δ = 0.22 [s, 6 H, Si(CH3)2], 0.88 (t, 3
H, J = 6.6 Hz, C11H22CH3), 0.99 [s, 9 H, SiC(CH3)3], 1.2–1.5 (m, 18
H, 9 CH2), 1.65 (m, 2 H, NHCH2CH2C10H21), 3.36 (dt, 2 H, J = 6.6,
5.4 Hz, NHCH2C11H23), 4.62 (t, 1 H, J = 5.4 Hz, NHC12H25), 6.90
(d, 2 H, J = 8.7 Hz, 2 Harom), 7.72 (d, 2 H, J = 8.7 Hz, 2 Harom), 7.91
(d, 1 H, J = 1.4 Hz, H3), 8.38 (d, 1 H, J = 1.4 Hz, H6).
13C NMR (50 MHz, CDCl3): δ = –4.4 (2 CH3Si), 14.1 (CH3), 18.3
[C(CH3)3], 22.7 (CH2), 25.7 [C(CH3)3], 27.0 (CH2), 29.3 (CH2),
29.4 (CH2), 29.6–29.9 (5 CH2), 31.9 (NHCH2CH2C10H21), 41.9
(NHCH2C11H23), 120.4 (2 CHarom), 126.6 (2 CHarom), 130.3 (Carom),
130.7 (C3), 138.5 (C6), 141.3 (C5), 153.1 (C2), 155.8 (COH).
MS (EI): m/z = 291 (M, 100).
Anal. Calcd for C18H17N3O 0.2 H2O (294.95): C, 73.29; H, 5.96; N,
14.24. Found: C, 73.37; H, 5.97; N, 13.86.
N-Benzyl-5-(p-hydroxyphenyl)-2-amino-1,4-pyrazine (15a)
Yellow solid; Rf : 0.28 (CH2Cl2–MeOH, 90:1); mp 160 °C.
1H NMR (300 MHz, CDCl3): δ = 4.60 (d, 2 H, J = 5.7 Hz,
NHCH2Ph), 4.92 (br s, 1 H, NHBn), 5.25 (br s, 1 H, OH), 6.90 (d, 1
H, J = 8.7 Hz, Harom), 7.24–7.39 (m, 4 H, Harom), 7.74 (d, 1 H,
J = 8.4 Hz, Harom), 7.94 (s, 1 H, H3), 8.41 (s, 1 H, H6).
MS (APCI): m/z = 470.5 (M + 1) (C28H47N3OSi).
13C NMR (75 MHz, CDCl3): δ = 46.1 (NHCH2Ph), 115.8 (2
CHarom), 127.1 (2 CHarom), 127.7 (2 CHarom), 127.8 (CHarom), 128.9
(2 CHarom), 129.9 (Carom), 130.8 (C3), 138.2 (C6), 138.5 (CHarom),
143.8 (C5), 152.6 (C2), 155.8 (COH).
N-Dodecanyl-5-(p-hydroxyphenyl)-2-amino-1,4-pyrazine (15g)
Yellow–orange solid; Rf 0.19 (cyclohexane–EtOAc, 5:2); mp 90–
92 °C.
1H NMR (300 MHz, CDCl3): δ = 0.88 (t, 3 H, J = 6.6 Hz, CH3),
1.26–1.45 (m, 18 H, 9 CH2), 1.65 (m, 2 H, NHCH2CH2C10H21), 3.36
(dt, 2 H, J = 6.6, 5.4 Hz, NHCH2C11H23), 4.60 (t, 1 H, J = 5.4 Hz,
NHC12H25), 6.89 (d, 2 H, J = 8.4 Hz, 2 Harom), 7.72 (d, 2 H, J = 8.4
Hz, 2 Harom), 7.94 (d, 1 H, J = 1.5 Hz, H3), 8.34 (d, 1 H, J = 1.5 Hz,
H6).
13C NMR (50 MHz, acetone-d6): δ = 14.3 (CH3), 23.3 (CH2), 27.8
(CH2), 30.2 (CH2), 30.3–30.4 (6 CH2), 32.6 (CH2), 41.9 (NHCH2),
116.3 (2 CHarom), 127.2 (2 CHarom), 130.3 (Carom), 132.4 (C3), 138.4
(C6), 141.0 (C5), 154.7 (C2), 158.1 (COH).
MS (APCI): m/z = 279.15 (M + 2), 278.32 (M + 1), 276.31 (M – 1)
(C17H15N3O).
N-Phenethyl-5-(p-hydroxyphenyl)-2-amino-1,4-pyrazine (15b)
Gummy yellow solid (hygroscopic compound); Rf 0.27 (CH2Cl2–
MeOH, 96:4).
1H NMR (300 MHz, CDCl3): δ = 2.95 (t, 2 H, J = 6.9 Hz,
CH2CH2Ph), 3.65 (t, 2 H, J = 6.9 Hz, NHCH2Bn), 4.70 (br s, 1 H,
NHCH2Bn), 6.86 (d, 2 H, J = 8.7 Hz, 2 Harom), 7.20–7.39 (m, 5 H,
5 Harom), 7.67 (d, 2 H, J = 8.7 Hz, 2 Harom), 7.89 (s, 1 H, H3), 8.33 (s,
1 H, H6).
MS (CI): m/z = 356.2 (M + 1).
13C NMR (75 MHz, CDCl3): δ = 35.7 (CH2CH2Ph), 43.1
(NHCH2Bn), 116.0 (2 CHarom), 126.7 (CHarom), 127.2 (2 CHarom),
128.8 (2 CHarom), 128.9 (2 CHarom), 129.1 (Carom), 130.8 (C3), 137.8
(CHarom), 138.7 (C6), 141.5 (C5), 152.8 (C2), 156.5 (COH).
Anal. Calcd for C22H33N3O: C, 74.32; H, 9.35; N, 11.82. Found: C,
74.07; H, 9.30; N, 11.79.
N-Hexyl-5-(p-tert-butyldimethylsilyloxyphenyl)-2-amino-1,4-
pyrazine (14e)
MS (APCI): m/z = 292.25 (M + 1) (C18H17N3O).
Yellow solid; Rf 0.3 (cyclohexane–EtOAc, 11:1); mp 99–101 °C.
N-Butyl-5-(p-hydroxyphenyl)-2-amino-1,4-pyrazine (15c)
Yellow solid; Rf 0.14 (cyclohexane–EtOAc, 10:3); mp 76.5–78 °C.
1H NMR (500 MHz, CDCl3): δ = 0.22 [s, 6 H, Si(CH3)2], 0.9 (t, 3
H, C5H10CH3), 0.99 [s, 9 H, SiC(CH3)3], 1.33 (m, 4 H, 2 CH2), 1.41
(m, 2 H, CH2), 1.65 (m, 2 H, NHCH2CH2C4H9), 3.36 (dt, 2 H,
J = 6.6, 5.4 Hz, NHCH2C5H11), 4.57 (t, 1 H, J = 5.4 Hz, NHC6H13),
6.90 (d, 2 H, J = 8.6 Hz, Harom), 7.72 (d, 2 H, J = 8.6 Hz, 2 Harom),
7.92 (d, 1 H, J = 1.4 Hz, H3), 8.38 (d, 1 H, J = 1.4 Hz, H6).
13C NMR (125 MHz, CDCl3): δ = –4.5 [Si(CH3)2], 13.9
(C5H10CH3), 18.1 [SiC(CH3)3], 22.5 (C4H8CH2CH3), 25.6
[SiC(CH3)3], 26.5 (CH2), 29.4 (CH2), 31.4 (CH2), 41.8 (NHCH2),
120.3 (2 CHarom), 126.5 (2 CHarom), 130.2 (C3), 130.5 (Carom), 138.4
(C6), 141.3 (C5), 152.9 (C2), 155.6 (COH).
1H NMR (300 MHz, CDCl3): δ = 0.96 (t, 3 H, J = 7.2 Hz, CH3),
1.38–1.48 (m, 2 H, CH2), 1.59–1.69 (m, 2 H, CH2), 3.33–3.39 (m, 2
H, NHCH2), 4.65 (br s, 1 H, NHBu), 6.89 (d, 2 H, J = 8.4 Hz, Harom),
7.70 (d, 2 H, J = 8.4 Hz, Harom), 7.92 (s, 1 H, J = 1.4 Hz, H3), 8.36
(s, 1 H, J = 1.4 Hz, H6).
13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 20.4 (CH2), 31.8
(CH2), 41.8 (NHCH2), 115.9 (2 CHarom), 127.1 (2 CHarom), 129.8
(Carom), 130.2 (C3), 138.5 (C6), 141.4 (C5), 153.0 (C2), 156.1 (COH).
MS (FAB+): m/z = 244.27 (M + 1) (C14H17N3O).
MS (APCI): m/z = 386.4 (M + 1) (C22H35N3OSi).
N-Isobutyl-5-(p-hydroxyphenyl)-2-amino-1,4-pyrazine (15d)
Yellow solid; Rf 0.40 (cyclohexane–EtOAc, 5:4); mp 166–168 °C.
N,N′-Bis(hexyl)-5-(p-tert-butyldimethylsilyloxyphenyl)-2-ami-
no-1,4-pyrazine (17e)
Gummy yellow solid; Rf 0.5 (cyclohexane–EtOAc, 11:1).
1H NMR (300 MHz, CDCl3): δ = 1.00 (d, 6 H, J = 6.6 Hz, 2 CH3),
1.88–1.95 [m, 1 H, CH2CH(CH3)2], 3.20 (t, 2 H, J = 6.9 Hz,
NHCH2), 4.72 (br s, 1 H, NH), 6.89 (d, 2 H, J = 8.7 Hz, 2 Harom),
7.70 (d, 2 H, J = 8.7, 2 Harom), 7.93 (s, 1 H, J = 1.4 Hz, H3), 8.36 (s,
1 H, J = 1.4 Hz, H6).
13C NMR (75 MHz, CDCl3): δ = 20.5 (2 CH3), 28.5
[CH2CH(CH3)2], 49.6 (NHCH2), 115.9 (2 CHarom), 127.1 (2
CHarom), 130.3 (C3 + Carom), 138.5 (C6), 141.6 (C5), 153.7 (C2),
156.2 (COH).
1H NMR (500 MHz, CDCl3): δ = 0.22 [s, 6 H, Si(CH3)2], 0.9 (t, 6
H, 2 C5H10CH3), 0.99 [s, 9 H, SiC(CH3)3], 1.32 (m, 12 H, 6 CH2),
1.61 (m, 4 H, 2 NHCH2CH2C4H9), 3.46 [t, 4 H, J = 6.6 Hz,
N(CH2C5H11)2], 6.89 (d, 2 H, J = 8.6 Hz, 2 Harom), 7.72 (d, 2 H,
J = 8.6 Hz, 2 Harom), 7.97 (d, 1 H, J = 1.4 Hz, H3), 8.42 (d, 1 H,
J = 1.4 Hz, H6).
13C NMR (125 MHz, CDCl3): δ = –4.5 [Si(CH3)2], 13.9 (2
C5H10CH3), 18.1 [SiC(CH3)3], 22.5 (2 C4H8CH2CH3), 25.6
[SiC(CH3)3], 26.6 (2 CH2), 27.5 (2 CH2), 31.6 (2 CH2), 48.5 (2
NHCH2C5H11), 120.3 (2 CHarom), 126.2 (2 CHarom), 128.4 (C3),
130.8 (Carom), 138.4 (C6), 139.1 (C5), 152.1 (C2), 155.6 (COH).
MS (APCI): m/z = 244.27 (M + 1) (C14H17N3O).
Synthesis 2003, No. 4, 513–522 ISSN 0039-7881 © Thieme Stuttgart · New York

520
P. Jeanjot et al.
PAPER
N-Benzyl-3,5-bis(p-methoxyphenyl)-2-amino-1,4-pyrazine
MS (APCI): m/z = 470.4 (M + 1) (C27H47N3OSi).
(19a)
N-Hexyl-5-(p-hydroxyphenyl)-2-amino-1,4-pyrazine (15e)
Yellow solid; Rf 0.44 (cyclohexane–EtOAc, 5:1); mp 102 °C.
Yellow solid; Rf 0.13 (cyclohexane–EtOAc, 7:3); mp 91–92 °C.
1H NMR (300 MHz, CDCl3): δ = 3.84 (s, 6 H, CH3), 4.66 (d, 2 H,
J = 5.5 Hz, NHCH2Ph), 5.27 (t, 1 H, J = 5.3 Hz, NHBn), 6.96 (d, 2
H, J = 8.9 Hz, Harom), 7.01 (d, 2 H, J = 8.9 Hz, Harom), 7.33 (m, 5 H,
1H NMR (500 MHz, CDCl3): δ = 0.9 (t, 3 H, C5H10CH3), 1.31 (m, 4
H, 2 CH2), 1.40 (m, 2 H, CH2), 1.61 (m, 2 H, NHCH2CH2C4H9),
3.35 (dt, 2 H, J = 5.4, 5.4 Hz, NHCH2C5H11), 4.63 (t, 1 H, J = 5.4,
NHC6H13), 5.86 (br s, 1 H, PhOH), 6.88 (d, 2 H, J = 8.7, 2 Harom),
7.70 (d, 2 H, J = 8.7, 2 Harom), 7.92 (d, 1 H, J = 1.5, H3), 8.36 (d, 1
H, J = 1.5, H6).
13C NMR (125 MHz, CDCl3): δ = 13.9 (C5H10CH3), 22.5
(C4H8CH2CH3), 26.5 (CH2), 29.4 (CH2), 31.4 (CH2), 41.8
(NHCH2), 115.7 (2 CHarom), 126.9 (2 CHarom), 129.6 (Carom), 130.5
(C3), 138.4 (C6), 141.3 (C5), 152.9 (C2), 156.1 (COH).
Harom), 7.71 (d, 2 H, J = 8.8 Hz, Harom), 7.88 (d, 2 H, J = 8.8 Hz,
Harom), 8.40 (s, 1 H, H6).
13C NMR (75 MHz, CDCl3): δ = 45.8 (NHCH2Ph), 55.5 (2 OCH3),
114.3 (2 CHarom), 114.7 (2 CHarom), 127.0 (2 CHarom), 127.4
(CHarom), 127.7 (2 CHarom), 128.8 (2 CHarom), 129.7 (2 Carom), 130.0
(2 CHarom), 136.4 (C6), 139.4 (Carom), 140.4 (C3), 141.1 (C5), 150.5
(C2), 159.7 (COCH3), 160.3 (COCH3).
MS (EI): m/z (%) = 397 (M, 100).
MS (APCI): m/z = 272.3 (M + 1) for C16H21N3O.
Anal. Calcd for C25H23N3O2: C, 75.50; H, 5.79; N, 10.57. Found: C,
75.46; H, 5.78; N, 10.41.
N,N′-Bis(hexyl)-5-(p-hydroxyphenyl)-2-amino-1,4-pyrazine
(18e)
Gummy yellow solid; Rf 0.4 (cyclohexane–EtOAc, 7:3).
N-Benzyl-3,5-bis(p-hydroxyphenyl)-2-amino-1,4-pyrazine
(21a)
Yellow solid; Rf 0.53 (cyclohexane–EtOAc, 5:2); mp 90–91 °C.
1H NMR (500 MHz, CDCl3): δ = 0.89 (t, 6 H, 2 C5H10CH3), 1.32
(m, 12 H, 6 CH2), 1.61 (m, 4 H, 2 NHCH2CH2C4H9), 3.46 [t, 4 H,
J = 6.6 Hz, N(CH2C5H11)2], 5.86 (br s, 1 H, PhOH), 6.89 (d, 2 H,
J = 8.7 Hz, 2 Harom), 7.73 (d, 2 H, J = 8.7 Hz, 2 Harom), 7.97 (d, 1 H,
J = 1.5 Hz, H3), 8.41 (d, 1 H, J = 1.5 Hz, H6).
13C NMR (125 MHz, CDCl3): δ = 13.9 (2 C5H10CH3), 22.5 (2
C4H8CH2CH3), 26.6 (2 CH2), 27.5 (2 CH2), 31.6 (2 CH2), 48.6 (2
NHCH2), 115.6 (2 CHarom), 126.6 (2 CHarom), 128.4 (C3), 130.4
(Carom), 138.4 (C6), 139.0 (C5), 152.2 (C2), 155.3 (COH).
1H NMR (300 MHz, acetone-d6): δ = 4.46 (d, 2 H, J = 6.0 Hz,
NHCH2Ph), 5.27 (t, 2 H, J = 6.0 Hz, NHBn), 6.66 (d, 2 H, J = 8.7
Hz, Harom), 6.72 (d, 2 H, J = 8.7 Hz, Harom), 7.05 (m, 5 H, Harom),
7.44 (d, 2 H, J = 8.7 Hz, Harom), 7.62 (d, 2 H, J = 8.8 Hz, Harom),
8.15 (s, 1 H, H6), 8.23 (br s, 1 H, OH), 8.47 (br s, 1 H, OH).
13C NMR (75 MHz, acetone-d6): δ = 45.6 (NHCH2Ph), 116.4 (2
CHarom), 116.6 (2 CHarom), 127.5 (3 CHarom), 128.4 (2 CHarom), 129.2
(2 CHarom), 129.9 (Carom), 130.3 (Carom), 131.0 (2 CHarom), 136.5
(C6), 140.3 (C3), 141.0 (Carom), 141.6 (C5), 151.5 (C2), 158.4 (COH),
159.2 (COH).
MS (APCI): m/z = 356.5 (M + 1) (C22H33N3O).
N-Decyl-5-(p-hydroxyphenyl)-2-amino-1,4-pyrazine (15f)
Gummy orange solid; Rf 0.2 (cyclohexane–EtOAc, 7:3).
MS (EI): m/z (%) = 369.1 (M, 100) (C23H19N3O2).
1H NMR (500 MHz, CDCl3): δ = 0.87 (t, 3 H, C9H18CH3), 1.26 (m,
8 H, 4 CH2), 1.31 (m, 4 H, 2 CH2), 1.40 (m, 2 H, CH2), 1.61 (m, 2
N-Hexyl-3,5-bis(p-tert-butyldimethylsilyloxyphenyl)-2-amino-
1,4-pyrazine (20e)
H, NHCH2CH2C8H17), 3.35 (dt,
2
H, J = 5.4, 5.4 Hz,
Yellow solid; Rf 0.5 (cyclohexane–EtOAc, 10:1); mp 130 °C.
NHCH2C9H19), 4.60 (t, 1 H, J = 5.4 Hz, NHC10H21), 5.86 (br s, 1 H,
PhOH), 6.89 (d, 2 H, J = 8.7 Hz, 2Harom), 7.72 (d, 2 H, J = 8.7 Hz,
1H NMR (500 MHz, CDCl3): δ = 0.21 [s, 6 H, Si(CH3)2], 0.25 [s, 6
H, Si(CH3)2], 0.88 (t, 3 H, J = 6.6 Hz, C5H10CH3), 0.99 [s, 9 H,
SiC(CH3)3], 1.01 [s, 9 H, SiC(CH3)3], 1.31 (m, 4 H, 2 CH2), 1.36 (m,
2 H, CH2), 1.59 (m, 2 H, NHCH2CH2C4H9), 3.41 (dt, 2 H, J = 5.5,
5.5 Hz, NHCH2C5H11), 4.91 (t, 1 H, J = 5.5 Hz, NHC6H13), 6.90 (d,
2 H, J = 8.6 Hz, Harom), 6.97 (d, 2 H, J = 8.6 Hz, Harom), 7.78 (d, 2
H, J = 8.6 Hz, Harom), 7.80 (d, 2 H, J = 8.6 Hz, Harom), 8.42 (s, 1 H,
H6).
Harom), 7.92 (d, 1 H, J = 1.5 Hz, H3), 8.36 (d, 1 H, J = 1.5 Hz, H6).
13C NMR (125 MHz, CDCl3): δ = 14.0 (C9H18CH3), 22.6
(C4H8CH2CH3), 26.9 (CH2), 29.4 (5 CH2), 31.8 (CH2), 41.8
(NHCH2), 115.7 (2 CHarom), 126.8 (2 CHarom), 129.9 (Carom), 130.2
(C3), 138.4 (CH6), 141.3 (C5), 152.9 (C2), 155.7 (COH).
MS (APCI): m/z = 328.5 (M + 1) (C20H29N3O).
13C NMR (125 MHz, CDCl3): δ = –4.5 [Si(CH3)2], –4.4 [Si(CH3)2],
13.9 (C5H10CH3), 18.1 [SiC(CH3)3], 18.2 [SiC(CH3)3], 22.4
(C4H8CH2CH3), 25.6 [2 SiC(CH3)3], 26.7 (CH2), 29.3 (CH2), 31.4
(CH2), 41.6 (NHCH2C5H11), 120.2 (2 CHarom), 120.5 (2 CHarom),
126.5 (2 CHarom), 129.6 (2 CHarom), 130.3 (Carom), 130.8 (Carom),
136.4 (C6), 140.1 (C3), 140.2 (C5), 150.6 (C2), 155.5 (COH), 156.3
(COH).
N-Tetradecyl-5-(p-hydroxyphenyl)-2-amino-1,4-pyrazine (15h)
Gummy orange solid; Rf 0.3 (cyclohexane–EtOAc, 7:3).
1H NMR (500 MHz, CDCl3): δ = 0.87 (t, 3 H, C13H26CH3), 1.26 (m,
16 H, 8 CH2), 1.31 (m, 4 H, 2 CH2), 1.40 (m, 2 H, CH2), 1.64 (m, 2
H, NHCH2CH2C12H25), 3.35 (dt,
2 H, J = 5.4, 5.4 Hz,
NHCH2C13H27), 4.60 (t, 1 H, J = 5.4 Hz, NHC14H29), 5.86 (br s, 1
H, PhOH), 6.89 (d, 2 H, J = 8.7 Hz, Harom), 7.72 (d, 2 H, J = 8.7 Hz,
MS (APCI): m/z = 592.5 (M + 1) (C34H53N3O2Si2).
Harom), 7.92 (d, 1 H, J = 1.5 Hz, H3), 8.36 (d, 1 H, J = 1.5 Hz, H6).
N-Hexyl-3,5-bis(p-hydroxyphenyl)-2-amino-1,4-pyrazine (21e)
Yellow solid; Rf 0.55 (cyclohexane–EtOAc, 1:1); mp 85 °C.
13C NMR (125 MHz, CDCl3): δ = 14.0 (C13H26CH3), 22.6
(C12H24CH2CH3), 26.9 (CH2), 29.4 (CH2), 29.5 (8CH2), 31.8 (CH2),
41.8 (NHCH2), 115.7 (2 CHarom), 126.8 (2 CHarom), 129.9 (Carom),
130.2 (C3), 138.4 (C6), 141.2 (C5), 152.9 (C2), 155.7 (COH).
1H NMR (500 MHz, CDCl3): δ = 0.88 (t, 3 H, J = 6.6 Hz,
C5H10CH3), 1.31 (m, 4 H, 2 CH2), 1.35 (m, 2 H, CH2), 1.60 (m, 2 H,
NHCH2CH2C4H9), 3.41 (dt, 2 H, J = 5.5, 5.5 Hz, NHCH2C5H11),
4.91 (t, 1 H, J = 5.5 Hz, NHC6H13), 5.15 (br s, 1 H, PhOH), 5.38 (br
s, 1 H, PhOH), 6.88 (d, 2 H, J = 8.6 Hz, Harom), 6.95 (d, 2 H, J = 8.6
Hz, Harom), 7.62 (d, 2 H, J = 8.6 Hz, Harom), 7.80 (d, 2 H, J = 8.6 Hz,
MS (APCI): m/z = 384.3 (M + 1) (C24H37N3O).
Harom), 8.36 (s, 1 H, H6).
13C NMR (125 MHz, CDCl3): δ = 13.9 (C5H10CH3), 22.5
(C4H8CH2CH3), 26.7 (CH2), 29.3 (CH2), 31.4 (CH2), 41.6
Synthesis 2003, No. 4, 513–522 ISSN 0039-7881 © Thieme Stuttgart · New York

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N-(Alkyl)-2-amino-1,4-pyrazine Derivatives: 3- and 3,5-p-Hydroxyphenyl-Substituted Compounds
521
(NHCH2C5H11), 115.5 (2 CHarom), 115.9 (2 CHarom), 126.9 (2
CHarom), 129.7 (Carom), 129.9 (2 CHarom), 130.4 (Carom), 136.3 (C6),
140.1 (C3 and C5), 150.7 (C2), 155.4 (COH), 156.2 (COH).
concentration 0.05%), then in phosphate buffer; they were assayed
at final concentrations of 2.5, 0.5 and 0.1 µM. Antioxidant efficien-
cy of the tested compounds was evaluated by the diminution of the
reaction rate and expressed in percentage of inhibition as follows:
Inh (%) = 100 – (Rinh/100 × Ro), where Rinh and Ro are rate of oxi-
dation in the presence and absence of inhibitor, respectively. Values
(in parentheses) represent means (± SD) of triplicate experiments.
MS (APCI): m/z = 364.3 (M + 1) (C22H25N3O2).
N-Decyl-3,5-bis(p-hydroxyphenyl)-2-amino-1,4-pyrazine (21f)
Gummy orange solid; Rf 0.65 (cyclohexane–EtOAc, 1:1).
1H NMR (500 MHz, CDCl3): δ = 0.88 (t, 3 H, J = 6.6 Hz,
C9H18CH3), 1.26 (m, 8 H, 4 CH2), 1.31 (m, 4 H, 2 CH2), 1.35 (m, 2
H, CH2), 1.59 (m, 2 H, NHCH2CH2C8H17), 3.41 (dt, 2 H, J = 5.5,
5.5 Hz, NHCH2C9H19), 4.91 (t, 1 H, J = 5.5 Hz, NHC10H21), 5.16
(br s, 1 H, PhOH), 5.38 (br s, 1 H, PhOH), 6.88 (d, 2 H, J = 8.6 Hz,
Harom), 6.95 (d, 2 H, J = 8.6 Hz, Harom), 7.61 (d, 2 H, J = 8.6 Hz,
Harom), 7.79 (d, 2 H, J = 8.6, Harom), 8.35 (s, 1 H, H6).
Lipophilicity Measurement by IAM Chromatography (Table 2)
Capacity factors (k′IAM) were established on an immobilized artifi-
cial membrane (IAM) column (IAM. PC DD2; Drug Discovery
HPLC column 30 × 4.6 mm; Regis Tech. Inc., Morton Grove, IL,
USA). The mobile phase consisted of different mixtures of phos-
phate buffer saline (pH 7.4) and MeCN. The given values are the
extrapolated values at 0% in MeCN.
13C NMR (125 MHz, CDCl3): δ = 14.0 (C9H18CH3), 22.6
(C8H16CH2CH3), 26.9 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (3 CH2),
31.8 (CH2), 41.6 (NHCH2C9H19), 115.5 (2 CHarom), 115.9 (2
CHarom), 126.9 (2 CHarom), 129.5 (Carom), 129.9 (2 CHarom), 130.3
(Carom), 136.2 (C6), 140.1 (C3 and C5), 150.6 (C2), 155.4 (COH),
156.3 (COH).
The measurements were made at UCB-Pharma, Braine l’Alleud,
Belgium.
Acknowledgement
This work was supported by the Walloon Government, Belgium
(convention No. 9713664) and the Fonds National de la Recherche
Scientifique (FNRS, Belgium).
The authors thank Dr. Luc Quéré (UCB) for the lipophilicity mea-
surements.
MS (APCI): m/z = 420.5 (M + 1) (C26H33N3O2).
N-Tetradecyl-3,5-bis(p-hydroxyphenyl)-2-amino-1,4-pyrazine
(21h)
Gummy orange solid; Rf 0.70 (cyclohexane–EtOAc, 1:1).
1H NMR (500 MHz, CDCl3): δ = 0.89 (t, 3 H, J = 6.6 Hz,
C13H26CH3), 1.28 (m, 16 H, 8 CH2), 1.31 (m, 4 H, 2 CH2), 1.35 (m,
2 H, CH2), 1.60 (m, 2 H, NHCH2CH2C12H25), 3.38 (dt, 2 H, J = 5.5,
5.5 Hz, NHCH2C13H25), 4.91 (t, 1 H, J = 5.5 Hz, NHC14H29), 5.15
(br s, 1 H, PhOH), 5.38 (br s, 1 H, PhOH), 6.84 (d, 2 H, J = 8.6 Hz,
References
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7.72 (d, 2 H, J = 8.6 Hz, Harom), 8.26 (s, 1 H, H6).
13C NMR (125 MHz, CDCl3): δ = 14.4 (C13H26CH3), 23.7
(C12H24CH2CH3), 28.1 (CH2), 30.4 (CH2), 30.7 (9 CH2), 42.4
(NHCH2C9H19), 116.5 (2 CHarom), 116.6 (2 CHarom), 127.9 (2
CHarom), 129.5 (Carom), 130.3 (Carom), 131.0 (2 CHarom), 136.8 (C6),
141.5 (C3), 142.4 (C5), 152.2 (C2), 158.6 (COH), 159.6 (COH).
MS (APCI): m/z = 476.4 (M + 1) (C30H41N3O2).
N,N′-Bis(hexyl)-3,5-bis(p-hydroxyphenyl)-2-amino-1,4-pyra-
zine (24e)
Gummy yellow solid; Rf 0.70 (cyclohexane–EtOAc, 1:1).
1H NMR (500 MHz, CDCl3): δ = 0.88 (t, 3 H, J = 6.6 Hz, 2
C5H10CH3), 1.16 (m, 8 H, 4 CH2), 1.22 (m, 4 H, 2 CH2), 1.45 (m, 4
H, 2 NHCH2CH2C4H9), 3.16 (dt, 4 H, J = 5.5, 5.5 Hz, 2
NHCH2C5H11), 4.93 (br s, 2 H, 2 PhOH), 6.89 (d, 2 H, J = 8.6 Hz,
Harom), 6.90 (d, 2 H, J = 8.6 Hz, Harom), 7.81 (d, 2 H, J = 8.6 Hz,
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Harom), 7.89 (d, 2 H, J = 8.6 Hz, Harom), 8.36 (s, 1 H, H6).
13C NMR (125 MHz, CDCl3): δ = 13.9 (2 C5H10CH3), 22.5 (2
C4H8CH2CH3), 26.7 (2 CH2), 27.4 (2 CH2), 31.4 (2 CH2), 49.9
[N(CH2C5H11)2], 115.1 (2 CHarom), 115.5 (2 CHarom), 127.1 (2
CHarom), 129.3 (2 CHarom), 130.1 (Carom), 132.7 (Carom), 134.5 (C6),
142.0 (C3), 142.1 (C5), 153.4 (C2), 153.4 (COH), 155.6 (COH).
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MS (APCI): m/z = 448.4 (M + 1) (C28H37N3O2).
Lipid Peroxidation Assay (Table 2)
A micellar solution of linoleic acid (0.16 mM) in phosphate buffer
(50 mM, pH 7.4) is incubated at 35 °C with AAPH [2,2′-azo-bis(2-
amidinopropane)dihydrochloride, 0.25 mM], in a microplate-based
spectrophotometer (Spectra MAX 190, Molecular Devices). The
rate of oxidation, i.e. the production of conjugated dienes by the re-
action of linoleate with peroxyl radicals, is monitored continuously
at 234 nm. Tested compounds were first dissolved in EtOH (final
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