A general and efficient route to 6-methyl-pyrazin-2-yl-amines: Alkylation of 2,6-dichloropyrazine via malonate derivatives

Article abstract of DOI:10.1002/jhet.5570450531

(Chemical Equation Presented) We have developed a convenient two-stage process for the synthesis of 6-methylpyrazine-2-yl-amines from commercially available materials. The procedure involves the synthesis of (6-chloro-pyrazin-2-yl)-acetic acid via arylati

Full text of DOI:10.1002/jhet.5570450531

Sep-Oct 2008
1451
A General and Efficient Route to 6-Methyl-pyrazin-2-yl-amines:
Alkylation of 2,6-Dichloropyrazine via Malonate Derivatives
Paul J.J. Colbon, Alison C. Foster, Melvyn E. Giles, Zakariya Patel
and John T. Singleton*
AstraZeneca, Process R&D Charnwood,
Bakewell Road, Loughborough, LE11 5RH
E-mail: John.Singleton@AstraZeneca.com
Received March 28, 2008
N
N
N
N
N
N
O
R1
Cl
Cl
Cl
N
OH
R2
We have developed a convenient two-stage process for the synthesis of 6-methylpyrazine-2-yl-amines
from commercially available materials. The procedure involves the synthesis of (6-chloro-pyrazin-2-yl)-
acetic acid via arylation of diethyl malonate and in situ hydrolysis/decarboxylation. A second
decarboxylation takes place under the subsequent amination conditions allowing simple and efficient
access to the intended pyrazines.
J. Heterocyclic Chem., 45, 1451 (2008).
Scheme 2
INTRODUCTION
Initial drug discovery route to 1.
We recently required a convenient synthesis of 6-
methyl-pyrazin-2-yl-amine 1, which was an important
intermediate in the synthesis of several compounds within
our drug development program. A number of routes to 1
have been described in the literature but none are
particularly efficient or amenable to large-scale
manufacture [1-3]. For example, a one-step procedure
starting from readily available 2-amino-6-chloropyrazine
had been employed within our Medicinal Chemistry
function, based on a nickel-catalysed Negishi coupling
with dimethylzinc (Scheme 1) [3].
NH2
+
N
O
O
N
NH3
Na2S2O5
HO
POCl3
1
O
NH2
N
N
Cl
2
3
intermediate 2-chloro-6-methylpyrazine 3 made this
synthesis, in our view, unsuitable for multi-kilo scale
manufacture.
We
therefore
sought
alternative
methodology for introduction of the methyl group into the
pyrazine nucleus.
Scheme 1
RESULTS AND DISCUSSION
Route to 1 via Negishi coupling.
There are a number of reports of displacement of
halogens from halopyrazines and halobenzopyrazines
with a variety of stabilized carbanions [4]. However we
were aware of only anecdotal reports of decarboxylation
N
N
N
Me2Zn
Cl
NH2
NiCl2(dppp)
N
NH2
1
of pyrazinyl acetic acids
4
derived from 2,6-
dichloropyrazine leading to alkyl substituted pyrazine
products (Scheme 3) [5,6]. Of particular note is the
adventitious decarboxylation of a molecule of type 4 (R3
= alkyl) upon treatment with triethylamine in ethyl acetate
at reflux, surprisingly mild conditions that presumably
owe their success to the electron-withdrawing nature of
the pyrazine ring (Scheme 3) [5].
This procedure could be used to produce multi-gram
quantities of 1 in 50 % yield after chromatographic
purification, and the conditions could be modified to
widen the scope significantly as reported recently [3]. The
main drawback with this process is the need for an excess
of the hazardous (pyrophoric) dimethylzinc reagent,
which would present significant challenges to scale up in
the longer term. To produce the early hundred-gram
quantities of 1 a reported synthetic route which formed
the pyrazine ring from glycinamide and pyruvic aldehyde
was used with an overall yield of 12 % (Scheme 2) [1].
Unfortunately, the capricious nature of the pyrazine
ring formation, the difficult isolations of 2-hydroxy-6-
Scheme 3
Decarboxylations of Pyrazin-2-yl-acetic acid.
N
N
CO2H
Cl
N
Cl
N
R3
4
R3
methylpyrazine
2
and the low-melting, volatile

1452
P. J. J. Colbon, A. C. Foster, M. E. Giles, Z. Patel and J. T. Singleton
Vol 45
These reports suggested to us that a novel alternative
route to 1 from commercially available 2,6-dichloro-
pyrazine might be feasible, via initial chloride
displacement with a malonate anion to produce 2-(6-
chloropyrazin-2-yl)-malonic acid diethyl ester 6 (Scheme
4). The second chloride displacement with ammonia and a
double decarboxylation would then complete the
synthesis. In practice we discovered that the sodium salt
of 2-(6-chloro-pyrazin-2-yl)-malonic acid 7 undergoes a
facile initial decarboxylation to give the highly crystalline
most efficient. However, minimizing the second
decarboxylation reaction, which produced 3, proved
difficult. Increasing the temperature and duration of the
reaction to achieve complete formation of 3 was possible,
but extensive decomposition was observed, and this
compound had already been deemed an undesirable
intermediate due to its poor physical properties.
5
The ester hydrolysis under basic conditions was
achieved at 20 °C, and at this lower temperature the
reaction was much more selective than any of the acidic
hydrolysis conditions screened. No evidence of double
decarboxylation was observed and under these conditions
minor non-acidic impurities were also removed via a
methyl isobutyl ketone wash prior to the acidification.
The use of sodium hydroxide solution (2 M) provided the
optimum balance of reaction rate, volume efficiency and
solubility for the hydrolysis reaction. The result was an
aqueous layer containing 7, which was added slowly to
hydrochloric acid (6 M), initiating the first
decarboxylation. The order of addition and the reaction
temperature (20-25 °C) were crucial to maintaining an
addition-rate controlled reaction and hence a controlled
evolution of carbon dioxide. The resulting acid 8 partially
precipitated from the mixture, but in order to maximize
yield and for ease of isolation, the product was extracted
into methyl isobutyl ketone and concentrated in vacuo.
The resulting crude solid was then purified by
crystallization from methyl tert-butyl ether.
(6-chloro-pyrazin-2-yl)-acetic acid
8 which is next
subjected both to the second decarboxylation and
amination in the same step. Whilst 5 is quite expensive on
a small-scale, large-scale supply costs are relatively low
and this two stage route in which 8 is the only isolated
intermediate had potential for further development and
scale-up as described below.
Scheme 4
Drug development route to 1.
O
N
N
O
N
NaH
THF
OEt
OEt
+
Cl
OEt
Cl
N
Cl
O
O
OEt
6
5
2M NaOH
N
In the final step, amination by displacement of chloride
as well as the second decarboxylation were achieved, by
treatment of 8 with aqueous ammonia in a sealed vessel at
180 °C. Water was added at the end of reaction, and the
ammonia removed by evaporation in vacuo to facilitate an
efficient extraction of the product into ethyl acetate. A
charcoal treatment of the organic layer, before
concentration in vacuo gave 1 as a pale orange solid in
good yield and >99% purity by GC. The compound was
subsequently used in our drug discovery program as an
intermediate without any further purification.
O
N
O
NH3
6M HCl
1
Cl
ONa
ONa
N
Cl
N
OH
8
O
7
Crude 2-(6-chloro-pyrazin-2-yl)-malonic acid diethyl
ester 6 was prepared by reaction of the sodium salt of
diethyl malonate (two equivalents) with 5 at reflux. The
excess sodium hydride and diethyl malonate were
required due to the relatively acidic proton of 6. A lower
conversion of
5 to product was achieved if two
In order to broaden the utility of our new process we
sought to synthesize a variety of 6-methyl-pyrazin-2-yl-
amines. To explore the scope and limitations of the
nucleophilic aromatic substitution of 8 with a range of
amines, a set of standard reaction conditions was required.
The aqueous amination conditions used in the synthesis of
1 were not suitable for many potential hydrophobic
amines. A short reaction screen was conducted to
establish a suitable set of conditions that promoted
amination. Initially five solvents of varying polarity, both
protic and aprotic, were chosen (N-methylpyrrolidinone,
sulfolane, isoamyl alcohol, diglyme and xylene) and two
amines (benzylamine and p-nitroaniline) were examined.
The high boiling solvents allowed reactions to be carried
out in conventional glassware, this coupled with the use
equivalents of sodium hydride were used with only one
equivalent of diethyl malonate. Following an acid quench,
the organic layer was partially concentrated in vacuo (to
remove THF) and to give a solution of 6 and the excess
diethyl malonate. Isolation of 6 was investigated, but even
after purification by chromatography the compound
remained an oil. Separating 6 from the excess diethyl
malonate in future was likely to require vacuum
distillation or chromatography, which would be both
expensive and time consuming on a multi-kilo scale.
Therefore, effort focused on developing hydrolysis
conditions using the mixture of diethyl malonate and 6.
Both acidic and basic conditions for the ester hydrolysis
were examined. Of the acidic conditions investigated, the
use of sulfuric acid in acetic acid (60 °C, 24 h) appeared

Sep-Oct 2008
A General and Efficient Route to 6-Methyl-pyrazin-2-yl-amines
1453
of aromatic amines facilitated reaction monitoring (by
HPLC) over different reaction times and temperatures.
The two amines chosen offered a range of nucleophilicity
which was designed to allow further differentiation of the
solvents performance, should similar conversions be
obtained in different solvents using an amine considered
to be a good nucleophile. The output from this screen
For each reaction,
8
was dissolved in N-
methylpyrrolidinone, 6 equivalents of the amine added
and the solution heated at 160 °C for 20 hours. Amines
that had a boiling point lower than 160 °C were
investigated under the same optimized conditions but in a
sealed vessel. The isolated yields obtained for these
reactions showed good correlation with the nuleophilicity
of the starting amine. Excellent yields have been obtained
for good nucleophiles such as benzylamine and
octylamine, whist the substituted aniline examples clearly
indicate the effect on the yield of reducing anilines
nucleophilicity with electron withdrawing groups.
A control experiment in which 8 was simply heated in
N-methylpyrrolidinone at 150 °C showed that the
decarboxylation is relatively fast, complete conversion to
3 being observed within 2 hours. Thus, the process
proceeds via initial formation of 3 in situ, followed by a
slower nucleophilic substitution of the chloride by the
amines.
indicated that N-methylpyrrolidinone (10 vol.),
6
equivalents of amine and a reaction temperature of 160 °C
for 20 hours was likely to ensure good conversion. The
excess amine could be recycled or lower equivalents
could be used successfully if the amine was valuable but
this would prolong reaction times.
In order to investigate the effect of both steric and
electronic properties for this nucleophilic aromatic
substitution and synthesize a range of potentially useful
pyrazines 9 - 17, nine amines were chosen. The range
included primary, secondary, aliphatic, cyclic and
aromatic amines (Table 1).
Finally we have shown that a substituted malonate, 2-
benzyl-malonic acid diethyl ester 18 will also react with
5. The resulting product was then hydrolysed, decarbox-
ylated and aminated using aniline, to demonstrate the
potential for further expansion of the range of amino-
pyrazines that can be synthesized (Scheme 5).
Table 1
Amination of (6-chloro-pyrazin-2-yl)-acetic acid 8.
Yield
(%)
Entry
1
Amine
NH
Product
N
53
9
N
N
Scheme 5
.HCl
Synthesis of a 2,6-pyrazine via substituted malonate 18.
N
2
3
61
77
N
10
11
CO2Et
NaH
NH2
EtO2C
N
H
N
+
5
CO2Et
CO2Et
Cl
N
THF
N
Ph
18
19
NH
Ph
N
N
.HCl
Bu4NOH
N
NH
4
5
6
75
82
87
12
13
14
N
N
N
N
N
N
CO2Na
CO2Na
Cl
N
N
20
NH
Ph
N
O
O
6M HCl
N
N
NH2
N
N
H
N
PhNH2
NMP
CO2H
Ph
N
Cl
N
N
H
N
7
8
9
82
39
0
15
16
17
22
21
N
H
N
NH2
Ph
Cl
N
N
Cl
2-Benzyl-malonic acid diethyl ester 18 was used to
generate the corresponding 2-benzyl-2-(6-chloro-pyrazin-
2-yl)-malonic acid diethyl ester 19, which could be
isolated as a crystalline solid. The subsequent hydrolysis
required the addition of tetrabutylammonium hydroxide
N
H
NH2
O2N
N
O2N
N
H
N
NH2

1454
P. J. J. Colbon, A. C. Foster, M. E. Giles, Z. Patel and J. T. Singleton
Vol 45
chloro-pyrazin-2-yl)-malonic acid, sodium salt 7 was then added
to 6 M hydrochloric acid (135 mL), maintaining a reaction
temperature of 20-25 °C to facilitate the decarboxylation. The
resulting 6-chloro-pyrazin-2-yl-acetic acid 8, was extracted into
methyl isobutyl ketone (130 mL), dried over magnesium sulfate,
filtered and evaporated in vacuo to give a yellow solid. The
resulting crude solid 22.4 g was then crystallised from methyl
tert-butyl ether to give 6-chloro-pyrazin-2-yl-acetic acid 8 as a
white solid, 15.4 g, 89.2 mmol (67 % yield based on 2,6-
as 19 appeared completely insoluble when subjected to
our standard sodium hydroxide (2 M), hydrolysis
conditions. The resulting intermediate 20 was again
decarboxylated without isolation to furnish 2-(6-chloro-
pyrazin-2-yl)-3-phenyl-propionic acid 21, whilst the
subsequent amination with aniline was carried out using
our standard conditions to produce the desired (6-
phenethyl-pyrazin-2-yl)-phenyl-amine 22. Although no
optimisation of this route was carried out this
demonstrates the potential scope for expansion beyond
methylpyrazine, via the use of other malonates or
carbanions.
In conclusion, we have demonstrated a new synthetic
route to 6-methyl-pyrazin-2-yl amines, in two stages via
an easily isolated intermediate from relatively cheap and
available starting materials. The new route has been used
to produce 1 on multigram scale giving an overall yield of
48 % and should be more amenable for further
development into a multi-kilo process than any currently
reported route [1-3]. The process is also suitable for a
range of amines giving access to a potentially useful
variety of 6-methyl-pyrazine-2-yl-amines. Finally the use
of a substituted malonate indicates the potential scope to
develop the syntheses of other 2,6-substituted pyrazines,
which may subsequently be investigated.
1
dichloropyrazine). Melting point: 120-121 °C. H NMR (400
MHz, dimethyl sulfoxide-d6): ꢀ 12.77 (1H, s), 8.71 (1H, s), 8.67
(1H, s), 3.88 (2H, s). 13C NMR (100 MHz, dimethyl sulfoxide-
d6) ꢀ 170.7, 151.2, 147.3, 143.8, 142.4, 40.0. ESI MS (m/z)
173/175 (M+H). HRMS (ESI): [M+H]+ calcd. for C6H6N2O2Cl:
173.0115, found: 173.0118. Anal. Calcd. for C6H5ClN2O2: C,
41.76; H, 2.92; N, 16.23. Found: C, 41.56; H, 2.97; N, 16.10.
6-Methyl-pyrazin-2-ylamine 1. To 6-chloro-pyrazin-2-yl-
acetic acid 8 (20.0 g, 115.9 mmol) was added 35 % aqueous
ammonia (120 mL) and the mixture was then placed in a sealed
vessel at 180 °C for 8 h (35 bar pressure observed). The mixture
was cooled to 20 °C and water (40 mL) was added before being
concentrated under vacuum to remove the ammonia. Water (40
mL) was then added to the residue before the product was
extracted into ethyl acetate (2 x 80 mL). The solution was
treated with charcoal (3 g) and stirred for 5 minutes before being
filtered. The resulting solution was then dried using magnesium
sulfate, filtered and evaporated to give 6-methyl-pyrazin-2-
ylamine 1 as a pale orange solid 9.0 g, 82.5 mmol (71 % yield
based on 6-chloro-pyrazin-2-yl-acetic acid). Melting point: 124-
125 °C. 1H NMR (400 MHz, dimethyl sulfoxide-d6): ꢀ 7.68 (1H,
s), 7.57 (1H, s), 6.27 (2H, br s), 2.21 (3H, s). 13C NMR (100
MHz, dimethyl sulfoxide-d6) ꢀ 155.2, 150.3, 130.6, 129.1, 20.7.
HRMS (ESI): [M+H]+ calcd. for C5H8N3: 110.0715, found:
110.0718. Anal. Calcd. for C5H7N3: C, 55.03; H, 6.47; N, 38.50.
Found: C, 54.91; H, 6.46; N, 38.17.
Optimised procedure for the synthesis of 6-methyl-
pyrazin-2-yl amines 9-17. The reagent amine (6 equiv) was
added to a solution of 8 (1.0 g, 5.8 mmol) in N-methyl-
pyrrolidinone (10 mL) and heated to 160 °C for 20 h. The
reaction mixture was purified by ion exchange column
chromatography using a Varian SCX column and an eluent of
methanol, followed by ammonia in methanol solution. The
product containing eluent was concentrated in vacuo and further
purified by chromatography on silica (particle size: 60A)
(eluent: either dichloromethane/methanol or ethyl acetate/
isohexane) to give the desired 6-methyl-pyrazin-2-yl amine.
When the product existed as an oil, it was converted into its
hydrochloride salt by addition of hydrochloric acid in methanol,
and the solid salt isolated by filtration.
EXPERIMENTAL
2-(6-Chloro-pyrazin-2-yl)-malonic acid diethyl ester 6. To
a suspension of sodium hydride [60 % dispersion in mineral oil]
(11.2 g, 279.1 mmol) in tetrahydrofuran (THF) (60 mL) at 0 °C
was added diethyl malonate (42.4 mL, 279.1 mmol) in THF (60
mL) followed by a solution of 2,6-dichloropyrazine 5 (20.0 g,
132.9 mmol) in THF (40 mL). The mixture was then heated to
reflux for 18 h before being allowed to cool and 2 M
hydrochloric acid (100 mL) added. The resulting two layers
were separated and the organic layer partially concentrated
under vacuum (removing the THF) to give a solution containing
2-(6-chloro-pyrazin-2-yl)-malonic acid diethyl ester 6 and
diethyl malonate.
The crude 2-(6-chloro-pyrazin-2-yl)-malonic acid diethyl
ester 6 can be purified by chromatography on silica eluting with
dichloromethane/isohexane (4/1) providing the compound as a
1
clear colourless oil. H NMR (400 MHz, dimethyl sulfoxide d6)
ꢀ 8.82 (1H, s), 8.76 (1H, s), 5.39 (1H, s), 4.20 (2 x 2H, q, J =
10.2 Hz), 1.20 (2 x 3H, t, J = 10.2 Hz). 13C NMR (100 MHz,
dimethyl sulfoxide-d6) ꢀ 166.1, 148.9, 147.2, 143.8, 143.7, 61.8,
56.5, 13.7. ESI MS (m/z) 273/275 (M+H). HRMS (ESI):
[M+H]+ calcd. for C11H14N2O4Cl: 273.0642, found: 273.0635.
Anal. Calcd. for C11H13ClN2O4: C, 48.45; H, 4.81; N, 10.27.
Found: C, 48.40; H, 5.10; N, 9.97.
6-Chloro-pyrazin-2-yl-acetic acid 8. The crude solution of
2-(6-chloro-pyrazin-2-yl)-malonic acid diethyl ester 6 (131
mmol) containing approximately one equivalent of diethyl
malonate was cooled to 10 °C and 2 M aqueous sodium
hydroxide (328 mL) added. After stirring for 24 h the mixture
was washed with methyl isobutyl ketone (200 mL) and the
organic layer discarded. The aqueous layer containing 2-(6-
Diethyl-(6-methyl-pyrazin-2-yl)-amine hydrochloride 9.
The title compound was obtained according to the general
procedure; the crude product was purified by chromatography
on silica eluting with dichloromethane/methanol (400/1) to give
the product oil, which was converted to its hydrochloride salt, a
yellow solid, 0.6 g, 3.1 mmol, yield 53 %. Melting point: 139-
140 °C. 1H NMR (400 MHz, dimethyl sulfoxide-d6) ꢀ 8.04 (1H,
s), 7.74 (1H, s), 3.56 (4H, q, J = 7.0 Hz), 2.40 (3H, s), 1.13 (6H,
t, J = 7.0 Hz). 13C NMR (100 MHz, dimethyl sulfoxide-d6) ꢀ
153.3, 152.8, 124.2, 122.5, 41.8, 21.4, 12.4. HRMS (ESI):
[M+H]+ calcd. for C9H16N3: 166.1344, found: 166.1340. Anal.
Calcd. for C9H16N3Cl: C, 53.59; H, 8.00; N, 20.83. Found: C,
53.72; H, 7.94; N, 21.00.

Sep-Oct 2008
A General and Efficient Route to 6-Methyl-pyrazin-2-yl-amines
1455
Isopropyl-(6-methyl-pyrazin-2-yl)-amine 10. The title
compound was obtained according to the general procedure; the
crude product was purified by chromatography on silica eluting
with dichloromethane/methanol (200/1) to give the product as a
brown solid, 0.6 g, 3.8 mmol, yield 64 %. Melting point: 72-73
(6-Methyl-pyrazin-2-yl)-phenylamine 15. The title
compound was obtained according to the general procedure; the
crude product was purified by chromatography on silica eluting
with ethyl acetate/isohexane (1/3) to give the product as a brown
solid, 0.9 g, 4.8 mmol, yield 82 %. Melting point: 115-116 °C.
1H NMR (400 MHz, dimethyl sulfoxide-d6) ꢀ 9.36 (1H, s), 8.04
(1H, s), 7.81 (1H, s), 7.7-7.6 (2H, m), 7.3-7.2 (2H, m), 7.0-6.9
(1H, m), 2.36 (3H, s). 13C NMR (75 MHz, dimethyl sulfoxide-
d6) ꢀ 151.5, 149.7, 140.8, 132.5, 131.5, 128.7, 121.1, 118.1,
21.0. HRMS (ESI): [M+H]+ calcd. for C11H12N3: 186.1031,
found: 186.1013. Anal. Calcd. for C11H11N3: C, 71.33; H, 5.99;
N, 22.69. Found: C, 71.07; H, 5.97; N, 22.46.
1
°C. H NMR (400 MHz, dimethyl sulfoxide-d6) ꢀ 7.66 (1H, s),
7.49 (1H, s), 6.75 (1H, d, J = 6.9 Hz), 4.0-3.9 (1H, m), 2.23 (3H,
s), 1.14 (6H, d, J = 6.5 Hz). 13C NMR (100 MHz, dimethyl
sulfoxide-d6) ꢀ 153.7, 150.0, 129.9, 129.4, 41.1, 22.3, 21.1.
HRMS (ESI): [M+H]+ calcd. for C8H14N3: 152.1188, found:
152.1168. Anal. Calcd. for C8H13N3: C, 63.55; H, 8.67; N, 27.79.
Found: C, 63.61; H, 8.61; N, 27.72.
(4-Chloro-phenyl)-(6-methyl-pyrazin-2-yl)-amine 16. The
title compound was obtained according to the general procedure;
the crude product was purified by chromatography on silica
eluting with dichloromethane/methanol (100/1) and treatment
with charcoal to give the product as a white solid, 0.5 g, 2.3
2-Methyl-6-piperidin-1-yl-pyrazine hydrochloride 11. The
title compound was obtained according to the general procedure;
the crude product was purified by chromatography on silica
eluting with dichloromethane/methanol (400/1) to give the
product oil, which was converted to its hydrochloride salt, a
yellow solid, 1.0 g, 4.5 mmol, yield 77 %. Melting point: 162-
163 °C. 1H NMR (400 MHz, dimethyl sulfoxide-d6) ꢀ 8.25 (1H,
s), 7.77 (1H, s), 3.7-3.6 (4H, m), 2.40 (3H, s), 1.7-1.5 (6H, m).
13C NMR (100 MHz, dimethyl sulfoxide-d6) ꢀ 154.1, 153.2,
124.5, 123.3, 45.0, 24.9, 23.9, 21.3. HRMS (ESI): [M+H]+
calcd. for C10H16N3: 178.1344, found: 178.1356. Anal. Calcd. for
C10N16N3Cl: C, 56.20; H, 7.55; N, 19.66. Found: C, 56.29; H,
7.51; N, 19.89.
1
mmol, yield 39 %. Melting point: 132-133 °C. H NMR (400
MHz, dimethyl sulfoxide-d6) ꢀ 9.52 (1H, s), 8.03 (1H, s), 7.85
(1H, s), 7.8-7.7 (2H, m), 7.4-7.3 (2H, m), 2.37 (3H, s). 13C NMR
(100 MHz, dimethyl sulfoxide-d6) ꢀ 151.1, 149.7, 139.8, 132.9,
131.6, 128.5, 124.4, 119.5, 21.0. HRMS (ESI): [M+H]+ calcd.
for C11H11N3Cl: 220.0642, found: 220.0638. . Anal. Calcd. for
C11H10N3Cl: C, 60.14; H, 4.59; N, 19.13. Found: C, 60.01; H,
4.57; N, 19.02.
2-Benzyl-2-(6-chloro-pyrazin-2-yl)-malonic acid diethyl
ester 19. To a suspension of sodium hydride [60 % dispersion in
mineral oil] (1.0 g, 24.2 mmol) in THF (15 mL) at 0 °C was
added 2-benzyl-malonic acid diethyl ester 18 (5.2 mL, 22.2
mmol) in THF (12 mL) followed by a solution of 2,6-
dichloropyrazine 5 (3.0 g, 20.1 mmol) in THF (6 mL). The
mixture was then heated to reflux for 18 h before being allowed
to cool to 25 °C and 2 M hydrochloric acid (15 mL) was added.
The resulting two layers were separated and the aqueous layer
was washed with methyl tert-butyl ether (30 mL). The combined
organic layers were washed with brine (15 mL), dried over
magnesium sulfate, filtered and evaporated in vacuo to give a
yellow oil. The compound was then purified by flash
chromatography on silica (particle size: 60 Å) eluting with
dichloromethane/isohexane (1/1) providing the compound as a
waxy solid, which was then crystallised from isohexane to give
the compound as a white solid 4.5 g, 12.4 mmol, yield 62 %.
Melting point: 61-62 °C. 1H NMR (400 MHz, dimethyl
sulfoxide-d6) ꢀ 8.46 (1H, s), 8.29 (1H, s), 7.2-7.1 (3H, m), 6.9-
6.8 (2H, m) 4.3-4.2 (2 x 2H, m), 3.70 (2H, s), 1.2-1.1 (2 x 3H,
m). 13C NMR (100 MHz, dimethyl sulfoxide-d6) ꢀ 167.5, 151.4,
146.5, 143.8, 143.0, 134.6, 130.0, 128.2, 127.3, 64.7, 62.0, 40.7,
13.6. HRMS (ESI): [M+H]+ calcd. for C18H20N2O4Cl: 363.1112,
found: 363.1099. Anal. Calcd. for C18H19N2O4Cl: C, 59.59; H,
5.28; N, 7.72. Found: C, 59.71; H, 5.28; N, 7.70.
2-(6-Chloro-pyrazin-2-yl)-3-phenyl-propionic acid 21. To a
solution of 2-benzyl-2-(6-chloro-pyrazin-2-yl)-malonic acid
diethyl ester 19 (4.0 g, 11.0 mmol) in THF (4 mL) was added 2
M aqueous sodium hydroxide (16.5 mL, 33.1 mmol) followed
by tetra-n-butylammonium hydroxide (10.5 mL, 16.2 mmol).
After stirring for 24 h the mixture was diluted with water (22.5
mL) and washed with methyl tert-butyl ether (22.5 mL) and the
organic layer discarded. The aqueous layer containing 2-benzyl-
2-(6-chloro-pyrazin-2-yl)-malonic acid, sodium salt 20 was then
added to 6 M hydrochloric acid (10.5 mL), maintaining a
reaction temperature of 20-25 °C to facilitate the decarbox-
ylation. The product was then extracted into methyl tert-butyl
2-Imidazol-1-yl-6-methyl pyrazine 12. The title compound
was obtained according to the general procedure; the crude
product was purified by chromatography on silica eluting with
dichloromethane/methanol (39/1) to give the product as a brown
solid, 0.7 g, 4.5 mmol, yield 75 %. Melting point: 93-94 °C. 1H
NMR (400 MHz, dimethyl sulfoxide-d6) ꢀ 9.01 (1H, s), 8.59
(1H, s), 8.54 (1H, s), 8.0-7.9 (1H, m), 7.2-7.1 (1H, m), 2.57 (3H,
s). 13C NMR (100 MHz, dimethyl sulfoxide-d6) ꢀ 152.4, 144.1,
142.3, 135.1, 132.0, 130.4, 116.4, 20.9. HRMS (ESI): [M+H]+
calcd. for C8H9N4: 161.0827, found: 161.0821. Anal. Calcd. for
C8H8N4: C, 59.99; H, 5.03; N, 34.98. Found: C, 59.97; H, 4.91;
N, 34.91.
4-(6-Methyl-pyrazin-2-yl)-morpholine 13. The title
compound was obtained according to the general procedure; the
crude product was purified by chromatography on silica eluting
with ethyl acetate/isohexane (1/3) to give the product as a pale
orange solid, 0.9 g, 4.8 mmol, yield 82 %. Melting point: 65-66
1
°C. H NMR (400 MHz, dimethyl sulfoxide-d6) ꢀ 8.10 (1H, s),
7.77 (1H, s), 3.7-3.6 (4H, m), 3.5-3.4 (4H, m), 2.31 (3H, s). 13C
NMR (100 MHz, dimethyl sulfoxide-d6) ꢀ 154.0, 150.0, 132.1,
127.9, 65.8, 44.3, 21.0. HRMS (ESI): [M+H]+ calcd. for:
C9H14N3O: 180.1137, found: 180.1138. Anal. Calcd. for
C9H13N3O: C, 60.32; H, 7.31; N, 23.45. Found: C, 60.19; H,
7.26; N, 23.41.
(6-Methyl-pyrazin-2-yl)-octylamine 14. The title compound
was obtained according to the general procedure; the crude
product was purified by chromatography on silica eluting with
ethyl acetate/isohexane (3/17) to give the product as an orange
1
solid, 1.1 g, 5.1 mmol, yield 87 %. Melting point: 34-35 °C. H
NMR (400 MHz, dimethyl sulfoxide-d6) ꢀ 7.68 (1H, s), 7.50
(1H, s), 6.85 (1H, t, J = 5.4 Hz), 3.3-3.2 (2H, m), 2.24 (3H, s),
1.5-1.4 (2H, m), 1.3-1.2 (10H, m), 0.9-0.8 (3H, m). 13C NMR
(100 MHz, dimethyl sulfoxide d6) ꢀ 154.4, 149.9, 129.6, 129.5,
40.0, 31.2, 28.7, 28.7, 28.6, 26.5, 22.0, 21.0, 13.9. HRMS (ESI):
[M+H]+ calcd. for C13H24N3: 222.1970, found: 222.1981. Anal.
Calcd. for C13H23N3: C, 70.54; H, 10.47; N, 18.98. Found: C,
70.75; H, 10.60; N, 18.69.

1456
P. J. J. Colbon, A. C. Foster, M. E. Giles, Z. Patel and J. T. Singleton
Vol 45
ether (2 x 22.5 mL) dried over magnesium sulfate, filtered and
evaporated in vacuo to give a yellow oil. The resulting crude oil
3.0 g was then crystallised from ethyl acetate/isohexane (1/10)
to give 2-(6-chloro-pyrazin-2-yl)-3-phenyl-propionic acid 21 as
a white solid, 2.2 g, 8.4 mmol, yield 68 %. Melting point: 91-92
°C. 1H NMR (400 MHz, dimethyl sulfoxide-d6): ꢀ 12.84 (1H, s),
8.66 (1H, s); 8.52 (1H, s) 7.3-7.2 (2H, m), 7.2-7.1 (3H, m); 4.29
(1H, dd J = 9.0, 6.9Hz), 3.39 (1H, dd J = 13.9, 6.9Hz), 3.16 (1H,
dd J = 13.9, 9.0Hz). 13C NMR (75 MHz, dimethyl sulfoxide-d6)
ꢀ 171.9, 154.2, 147.5, 143.3, 142.7, 138.3, 128.8, 128.2, 126.3,
51.3, 36.2. HRMS (ESI): [M+H]+ calcd. for C13H12N2O2Cl:
263.0587, found: 263.0593. Anal. Calcd. for C13H11N2O2Cl: C,
59.44; H, 4.22; N, 10.66. Found: C, 59.49; H, 4.21; N, 10.48.
(6-Phenethyl-pyrazin-2-yl)-phenyl-amine 22. Aniline (2.1
mL, 22.8 mmol) was added to a solution of 21 (1.0 g, 3.8 mmol)
in N-methylpyrrolidinone (10 mL) and heated to 160 °C for 20
h. The reaction mixture was purified by ion exchange column
chromatography using a Varian SCX column and an eluent of
methanol, followed by ammonia in methanol solution. The
product containing eluent was concentrated in vacuo and further
purified by chromatography on silica (particle size: 60A) eluting
with ethyl acetate/isohexane (1/3) to give the product as a brown
solid. The solid was then crystallised from ethyl acetate/
isohexane (1/10) to give a white solid 0.6 g, 2.2 mmol, yield 57
128.3, 128.2, 125.9, 121.1, 118.1, 35.8, 34.2. HRMS (ESI):
[M+H]+ calcd. for C18H18N3: 276.1501, found: 276.1497. Anal.
Calcd. for C18H17N3: C, 78.52; H, 6.22; N, 15.26. Found: C,
78.41; H, 6.18; N, 15.00.
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sulfoxide d6) ꢀ 9.36 (1H, s), 8.04 (1H, s), 7.71 (1H, s), 7.70 (2H,
d J = 7.7Hz), 7.35-7.20 (6H, m), 7.2-7.1 (1H, m), 6.94 (1H, t J =
7.7Hz) 3.08-2.93 (4H, m). 13C NMR (100 MHz, dimethyl
sulfoxide d6) ꢀ 152.4, 151.6, 141.1, 140.8, 132.4, 131.9 128.7,