Synthesis of 4H-pyrazino[1,2-a]pyrimidine-4,9(8H)-diones and imidazo[1,2-a]pyrazin-8(7H)-ones

Article abstract of DOI:10.1055/s-0032-1317686

A facile method of synthesis of 4H-pyrazino[1,2-a]-pyrimidine-4,9(8H)- diones and imidazo[1,2-a]pyrazin-8(7H)-ones from the corresponding 3-amino-2(1H)-pyrazinones is described. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317686

LETTER
▌2935
lSetyternthesis of 4H-Pyrazino[1,2-a]pyrimidine-4,9(8H)-diones and Imidazo[1,2-
a]pyrazin-8(7H)-ones
Synthesis of Pyrimidine-4,9(8H)-diones and Pyrazin-8(7H)-ones
Piotr Raubo,*a,b Neal Ladwaa,c
a
AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK
E-mail: piotr.raubo@astrazeneca.com
b
AstraZeneca R&D, Alderley Park, Macclesfield, SK10 4TG, UK
c
Department of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
Received: 06.09.2012; Accepted after revision: 02.11.2012
Conceptually, 1 can be disconnected into two fragments,
Abstract: A facile method of synthesis of 4H-pyrazino[1,2-a]-
a 3-amino-2(1H)-pyrazinone 2 and a β-keto ester 3 in a
pyrimidine-4,9(8H)-diones and imidazo[1,2-a]pyrazin-8(7H)-ones
retro Conrad–Limpach condensation (Scheme 1).3 We
postulated that the 3-amino-2(1H)-pyrazinone 2 might be
accessible by the selective manipulation of 3,5-dibromo-
2(1H)-pyrazinone 6 capitalising on differences in reactiv-
from the corresponding 3-amino-2(1H)-pyrazinones is described.
Key words: heterocyclic compounds, bicyclic compounds,
Conrad–Limpach condensation, parallel synthesis
ity of both halogen atoms in the 3,5-dibromopyrazinone
ring.4 In turn, 6 should be easily synthesised in one step
Small aromatic heterocyclic ring systems play a pivotal
from the α-aminonitrile 7, a product of the three-compo-
role in the development of new drug candidates. To date,
nent Strecker reaction between the corresponding amine,
from the chemical space of 23,895 unique small hetero-
aldehyde and hydrogen cyanide. This short sequence
aromatic rings only about 7% have been synthesised.1 As
would allow a straightforward diversification at the 1- and
part of one of our ongoing medicinal chemistry pro-
6-positions of the pyrazinone ring (Scheme 1).
grammes we were interested in examining bicyclic het-
As a starting material for our model studies we chose
commercially available substituted α-aminonitriles 8a–c
(8a: R4 = H; 8b: R4 = Ph; 8c: R4 = i-Pr) which, on treat-
ment with an excess of oxalyl bromide in dichlorometh-
ane in the presence of a catalytic amount of DMF,
provided the corresponding 3,5-dibromo-2(1H)-pyrazi-
nones 9a–c in 47–53% yield (Scheme 2). Regioselective
nucleophilic substitution of the imidoyl bromine at the 3-
position of the pyrazinone ring in 9a–c using a 35% aque-
ous solution of ammonia in 1,4-dioxane gave the expected
erocyclic ring systems such as 1 (Scheme 1). To our
surprise a literature search revealed only one patent men-
tioning preparation of a single compound having such a
heterocyclic ring system.2 To support our medicinal
chemistry project, we were interested in a facile synthesis
of diverse analogues of 1. In this paper, we would like to
report results of our work on the development of the syn-
thesis of 4H-pyrazino[1,2-a]pyrimidine-4,9(8H)-dione
(1) and imidazo[1,2-a]pyrazin-8(7H)-one (5) ring sys-
tems.
O
R
R2
R1
X
R2
R1
O
R3
R3
O
N
R3
R2
R4
R5
R2
R1
R4
R5
R4
R5
O
3
O
4
N
N
N
R1
N
N
N
N
NH2
O
O
O
1
2
5
Br
R4
R5
R4
R5
CN
NH
N
+
(COBr)2
N
Br
O
7
6
Scheme 1 Diversification of the pyrazinone ring; since two different heterocyclic ring systems are discussed here, R group numbering has been
set to allow straightforward reading and do not reflect IUPAC numbering of the corresponding heterocycle
SYNLETT 2012, 23, 2935–2938
Advanced online publication: 28.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317686; Art ID: ST-2012-D0746-L
© Georg Thieme Verlag Stuttgart · New York

2936
P. Raubo, N. Ladwa
LETTER
Br
O
Br
O
R4
Ph
CN
NH
R4
Ph
R4
Ph
R4
Ph
R4 = H for 8a, 9a, 10a, 11a
a
c
b
N
N
N
R
R
4 = Ph for 8b, 9b, 10b, 11b
4 = i-Pr for 8c, 9c, 10c, 11c
N
N
N
Br
NH2
NH2
O
8a–c
9a (53%)
9b (51%)
9c (47%)
10a (77%)
10b (75%)
10c (86%)
11a (83%)
11b (89%)
11c (100%)
Scheme 2 Reagents and conditions: (a) (COBr)2, CH2Cl2, cat. DMF (47–53%); (b) NH3, 1,4-dioxane–H2O, r.t. (75–86%); (c) HCOONH4, Pd/C,
i-Pr2NEt, EtOH, reflux, (83–100%).
3-amino-5-bromo-2(1H)-pyrazinones 10a–c in good
yields (75–86%). Subsequent hydrogenation of the vinyl-
ic bromine at the 5-position under hydrogen transfer con-
ditions using ammonium formate in the presence of a
catalytic amount of palladium on charcoal smoothly af-
forded the required 3-amino-2(1H)-pyrazinone deriva-
tives 11a–c in excellent yields (83–100%).
O
R4
Ph
O
N
R4
Ph
R2
R1
R2
R1
N
a
+
N
RO
NH2
N
N
O
O
O
11a–c
3a–l
12a–n
NH
N
The Conrad–Limpach condensation of β-keto esters and
various amino heterocycles is a well-established reac-
tion.3 The standard procedure for this transformation in-
volves heating a β-keto ester with a corresponding amino
heterocycle in acidic medium (e.g. acetic acid or poly-
phosphoric acid).5 When we subjected 3-amino-2(1H)-
pyrazinone 11a to reaction with methyl 3-oxopentanoate
(3a) in glacial acetic acid we were pleased to observe for-
mation of the expected bicyclic product 12a with good
conversion (Scheme 3). However, when the more sterical-
ly demanding methyl 4-methyl-3-oxopentanoate (3b) was
used, the reaction was less effective leading to a signifi-
cant proportion of 1-phenylpyrazine-2,3(1H,4H)-dione
(13) which results from hydrolysis of the starting pyrazi-
none 11a. We assumed that this side reaction is proceed-
ing via initial N-acetylation of the amino group in 11a
making the 3-position more susceptible towards nucleo-
philic substitution. To avoid this side reaction, we opti-
mised reaction conditions by screening a range of acidic
promoters [acetic acid, methanesulfonic acid, Amberlyst
15 resin, Montmorillonite K 10, zinc(II) bromide, trimeth-
ylsilyl chloride, pyridinium p-toluenosulfonate, poly-
Ph
O
O
13
Scheme 3 Reagents and conditions: (a) β-keto ester 3a–l (10 equiv),
MsOH (1 equiv), MeCN, MW, 180 °C, (25–100%).
4,9(8H)-diones 12a–n in moderate to excellent isolated
yields (Table 1). In general, the reaction was completed
after 30 minutes. However, for more sterically hindered β-
keto esters (3b, 3g) prolonged reaction times were re-
quired to achieve good conversions. For pyrazinones
bearing a substituent at the 6-position (11b, 11c) better cy-
clisation yields were achieved in comparison to unsub-
stitued analogue 11a (e.g. 83% for the product 12l versus
63% for the product 12b). For the less accessible β-keto
ester 3l, 5.4 equivalents of β-keto ester were employed,
giving a significantly lower isolated yield of the corre-
sponding product 12n (25%). Heteronuclear multiple
quantum coherence (HMQC), heteronuclear multiple
bond coherence (HMBC) and NOE NMR experiments
were used to confirm the proposed structures of 12a and
12b.
phosphoric
acid,
scandium(III)
Unfortunately, our attempts to perform the condensation
of 5-substituted 3-amino-1-phenylpyrazin-2(1H)-ones 14
(R3 = Br, Ph)7 with 3a under these conditions failed to pro-
vide the requisite cyclisation product 15 (R = Br, Ph;
Scheme 4). This might be due to reduced nucleophilicity
and/or increased steric hindrance of 5-substituted 3-ami-
no-1-phenylpyrazin-2(1H)-ones.
trifluoromethanesulfonate] and solvents (acetic acid, ace-
tonitrile, DMF, ethanol, 1,4-dioxane, DMSO, 1,2-dichlo-
robenzene, N-methylpyrrolidine, 1,2-dichloroethane] in
addition to varying reaction temperature and stoichiome-
try of reagents. As a result of this optimisation, we found
that heating the 3-amino-2(1H)-pyrazinone 11a with ten
equivalents of 3b in anhydrous acetonitrile in the presence
of one equivalent of methanesulfonic acid under micro-
wave irradiation at 180 °C afforded the required 4H-pyr-
azino[1,2-a]pyrimidine-4,9(8H)-dione 12b in 63%
isolated yield (Scheme 3, Table 1, entry 2).6 When a cata-
lytic amount of methanesulfonic acid was used the reac-
tion did not proceed to completion.
R
R
O
O
O
a
N
N
MeO
+
N
N
Ph
N
Ph
N
O
O
14
3a
15
To investigate the scope of this cyclisation, a range of β-
keto esters 3a–l was employed using these conditions pro-
viding the corresponding 4H-pyrazino[1,2-a]pyrimidine-
Scheme 4 Reagents and conditions: (a) 14 (R = Br, Ph), β-keto ester
3a (10 equiv), MsOH (1 equiv), MeCN, MW, 180 °C.
Synlett 2012, 23, 2935–2938
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Pyrimidine-4,9(8H)-diones and Pyrazin-8(7H)-ones
2937
Table 1 Synthesis of 4H-Pyrazino[1,2-a]pyrimidine-4,9(8H)-diones 12a–n (Scheme 3)
β-Keto ester
R
R1
R2
11
R4
Product
Reaction time (min) Yield (%)a
3a
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
H
H
H
H
Ph
H
H
H
Bn
H
H
H
11a
11a
11a
11a
11a
11a
11a
11a
11a
11b
11c
11c
11a
11a
H
12a
12b
12c
12d
12e
12f
30
90
30
30
30
30
90
30
30
30
30
30
30
45
89
63
61
64
60
47
48
46
51
93
100
83
58
25
3b
i-Pr
H
3c
CF3
H
3d
Ph
H
3e
Me
H
3f
c-Pr
H
3g
t-Bu
2-furyl
Me
H
12g
12h
12i
3h
H
3i
H
3j
Me
Ph
i-Pr
i-Pr
H
12j
3j
Et
Me
12k
12l
3b
Me
Me
Me
i-Pr
3k
-(CH2)3-
-CH2SCH2-
12m
12n
3lb
H
a Isolated yield.
b Amount of 3l used was 5.4 equiv.
R2
In parallel, we also examined the reaction of 11a with α-
halo ketones 4a–g (Scheme 5, Table 2). We found that
treatment of 11a with 1-bromo-3,3-dimethylbutanone
(4a) in acetonitrile under microwave irradiation at 170 °C
in the presence of triethylamine provided the expected im-
idazo[1,2-a]pyrazin-8(7H)-one 16a in 63% yield (Table
2, entry 1).
R4
R4
Ph
R2
R1
4a–g
a
N
X
N
R1
+
N
N
Ph
NH2
N
O
O
O
11a–c
16a–k
Scheme 5 Reagents and conditions: (a) α-halo ketone 4a–g (1.2
equiv), Et3N (1.2 equiv), MeCN, MW, 170 °C
Table 2 Synthesis of Imidazopyrazin-8(7H)-ones 16a–k from 11a and 11c (Scheme 5)
α-Halo ketone
X
R1
R2
11
R4
Product
Reaction time (min) Yield (%)a
4a
Br
Br
Br
Br
Br
Cl
Cl
Cl
Br
Br
t-Bu
Ph
H
11a
11a
11a
11c
11a
11a
11a
11c
11a
11c
H
16a
16b
16c
16d
16f
16g
16h
16i
45
45
45
60
30
60
60
60
60
60
63
55
63
44
65
72
56
51
62
91
4b
H
H
4c
c-Pr
H
H
4c
c-Pr
H
i-Pr
H
4d
4-MeOC6H4
3-THPb
Me
H
4e
H
H
4f
H
H
4f
Me
H
i-Pr
H
4g
Ph
Me
Me
16j
16k
4g
Ph
i-Pr
a Isolated yield.
b Tetrahydro-2H-pyran-3-yl.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2935–2938

2938
P. Raubo, N. Ladwa
LETTER
mmol) were dissolved in anhyd MeCN (1.2 mL) and sealed
into a microwave tube. The reaction was heated at 180 °C
over a period of 30 min within the microwave reactor (see
ref. 12). The crude product was purified by flash silica
chromatography (elution gradient 0–100% EtOAc in
isohexane) to afford 2-methyl-8-phenyl-4H-pyrimido[1,2-
a]pyrazine-4,9(8H)-dione (12a) as a white solid (124 mg,
89%); mp 238.5–239.2 °C. 1H NMR (400 MHz, CDCl3): δ =
2.53 (s, 3 H), 6.55 (s, 1 H), 6.90 (d, J = 6.4 Hz, 1 H), 7.35–
7.60 (m, 5 H), 7.76 (d, J = 6.4 Hz, 1 H). 13C NMR (126 MHz,
CDCl3): δ = 24.49, 103.58, 111.92, 120.18, 125.78, 129.08,
129.71, 139.20, 144.66, 154.61, 157.54, 164.56. HRMS
(ESI+): m/z [M + H+] calcd for C14H11N3O2: 254.0924;
found: 254.0938.
Several imidazo[1,2-a]pyrazin-8(7H)-ones 16a–k were
prepared by condensation of 11a and 11c with selected α-
halo ketones 4a–g using the procedure described above to
afford the corresponding substituted imidazo[1,2-a]pyr-
azin-8(7H)-ones 16a–k in moderate to excellent yields
(44–91%).8 Since two regioisomers are possible, the
structures of compounds 16a, 16h and 16j were con-
firmed using HMQC, HMBC and NOE NMR experi-
ments.9 Imidazo[1,2-a]pyrazin-8(7H)-ones are found in a
number of biologically active compounds10 and have pre-
viously been prepared using different routes.10a,b,11
In conclusion, a facile method of synthesis of 4H-pyr-
azino[1,2-a]pyrimidine-4,9(8H)-diones 1 from the corre-
sponding 3-amino-2(1H)-pyrazinone and β-keto ester has
been developed. The condensation of 3-amino-2(1H)-pyr-
azinones with α-halo ketones provided imidazo[1,2-
a]pyrazin-8(7H)-ones 5. Procedures developed for both
condensation reactions fit well the requirements of paral-
lel synthesis coupled with automated purification tech-
niques allowing the rapid generation of a diverse set of
analogues for biological evaluation. 4H-Pyrazino[1,2-
a]pyrimidine-4,9(8H)-dione and imidazo[1,2-a]pyrazin-
8(7H)-one can serve as useful templates in the search for
new drug candidates.
(7) 3-Amino-1,5-diphenylpyrazin-2(1H)-one (14; R = Ph) was
obtained in a Suzuki cross-coupling reaction between 3-
amino-5-bromo-1-phenylpyrazin-2(1H)-one (10a) and
phenylboronic acid in 42% yield.
(8) A Representative Procedure for the Preparation of
Imidazo[1,2-a]pyrazin-8(7H)-ones 16a–k; 2,7-
Diphenylimidazo[1,2-a]pyrazin-8(7H)-one (16b): 3-
Amino-1-phenylpyrazin-2(1H)-one (11a; 100 mg, 0.53
mmol), 2-bromo-1-phenylethanone (4b; 133 mg, 0.67
mmol) and Et3N (0.093 mL, 0.67 mmol) were dissolved in
anhyd MeCN (1.2 mL) and sealed into a microwave tube.
The reaction was heated to 170 °C over a period of 45 min in
the microwave reactor (see ref. 12). The solid was filtered
off, washed with Et3N and recrystallised from MeCN to
afford 2,7-diphenylimidazo[1,2-a]pyrazin-8(7H)-one (16b)
as white crystals (85 mg, 55%); mp 304.9–306.9 °C. 1H
NMR (400 MHz, DMSO-d6): δ = 7.20 (d, J = 5.9 Hz, 1 H),
7.35 (t, J = 7.3 Hz, 1 H), 7.43–7.59 (m, 7 H), 7.65 (d, J = 5.9
Hz, 1 H), 7.94 (dd, J = 8.2, 1.0 Hz, 2 H), 8.33 (s, 1 H). HRMS
(ESI+): m/z [M + H+] calcd for C18H13N3O: 288.1131; found:
288.1134.
Acknowledgment
This work was carried out as a MChem project sponsored by the De-
partment of Medicinal Chemistry, AstraZeneca R&D Charnwood
and the Department of Chemistry of Loughborough University. The
authors would like to thank Dr Tom McInally, Dr Jamie Scott and
Mr Richard Evans for their assistance with manuscript preparation.
(9) For example, in a NOE experiment irradiation of the proton
at the 5-position of imidazo[1,2-a]pyrazin-8(7H)-one ring in
16a and 16j resulted in enhancement of R2 proton signal in
compound 16a (R2 = H) and in the case of 16j (R2 = Me) the
protons of the methyl group.
(10) (a) Goodacre, S. C.; Hallett, D. J.; Carling, R. W.; Castro, J.
L.; Reynolds, D. S.; Pike, A.; Wafford, K. A.; Newman, R.;
Atack, J. R.; Street, L. J. Bioorg. Med. Chem. Lett. 2006, 16,
1582. (b) Dwyer, M. P.; Paruch, K.; Alvarez, C.; Doll, R. J.;
Keertikar, K.; Duca, J.; Fischmann, T. O.; Hruza, A.;
Madison, V.; Lees, E.; Parry, D.; Seghezzi, W.;
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(6) Representative Procedure for the Preparation of 4H-
Pyrazino[1,2-a]pyrimidine-4,9(8H)-diones 12a–n; 2-
Methyl-8-phenyl-4H-pyrimido[1,2-a]pyrazine-4,9(8H)-
dione (12a): 3-Amino-1-phenylpyrazin-2(1H)-one (11a;
100 mg, 0.53 mmol), methyl 3-oxobutanoate (3a; 0.576 mL,
5.34 mmol) and methanesulfonic acid (0.035 mL, 0.53
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(12) Single-mode CEM Explorer and Biotage Initiator automated
microwave reactors were used.
Synlett 2012, 23, 2935–2938
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