Stereoselective epoxidation and bromoalkoxylation with 3-ylidenepyrazine-2,5-diones

Article abstract of DOI:10.1055/s-2003-36259

3-Ylidenepyrazine-2,5-diones 1 were stereoselectively epoxidsed by dimethyldioxirane giving access to spirooxiranes 2 and diols 3. Bromohydroxylation and bromoalkoxylation of 3-ylidenepyrazine-2,5-diones 1 produced high yields of optically active 3-(1-bro

Full text of DOI:10.1055/s-2003-36259

PAPER
67
Stereoselective Epoxidation and Bromoalkoxylation with 3-Ylidenepyrazine-
2,5-diones
A
ddition Reaction
n
s
with 3-Ylid
n
enepyrazine
e
a
Institut für Chemie, Humboldt-Universität Berlin, 12489 Berlin, Germany
Fax +49(30)20937552; E-mail: liebscher@chemie.hu-berlin.de
b
Institut für Anorganische und Analytische Chemie, Technische Universität Braunschweig, Postfach 3329,
38023 Braunschweig, Germany
Received 24 June 2002; revised 30 October 2002
dimethyldioxirane. The higher susceptibility to ring-
opening can be explained by the facile formation of N-
acyliminium salts 11 (Figure 1), if no electron-withdraw-
ing group R2 is attached to the nitrogen atom. The stereo-
Abstract: 3-Ylidenepyrazine-2,5-diones 1 were stereoselectively
epoxidsed by dimethyldioxirane giving access to spirooxiranes 2
and diols 3. Bromohydroxylation and bromoalkoxylation of 3-
ylidenepyrazine-2,5-diones 1 produced high yields of optically ac-
tive 3-(1-bromoalkyl)pyrazine-2,5-diones 4 with a 3-hydroxy or 3- chemical mode of formation of epoxides 2 was proved by
X-ray crystal analysis of compound 2c.2 All compounds 2
alkoxy function, respectively. Whereas direct hydrogenation of ep-
oxides 2 afforded epimeric mixtures of 3-(1-hydroxyalkyl)pyra-
zine-2,5-diones 5 and 6, the highly stereoselective transformation
into 5 was possible by primary acid cleavage of the oxirane ring fol-
lowed by hydrogenation of the resulting keto-enol mixtures 7/8.
Table 1 Yields of Products 2–8
Key words: epoxidation, pyrazine-2,5-diones, hydrogenations,
amino acid derivatives
Product
2a
R1
R2
R3
–
Yield (%)
Me
i-Pr
Ph
PhCO
PhCO
MeCO
MeCO
95
95
56
84
2b
–
3-Ylidenepyrazine-2,5-diones (3-ylidene-2,5-diketopip-
erazines) have found wide application in the synthesis of
derivatives of non-natural amino acids.1 Their dehy-
droamino acid motif allows a variety of additions to the
C–C double bond. Our preliminary investigations into the
possibility of epoxidation of 3-ylidenepyrazine-2,5-di-
ones 1 revealed that the powerful reagent dimethyldiox-
irane allowed the synthesis of the corresponding
spirooxiranes 2, which represent configurationally stable
-keto acid derivatives.2 Full experimental details, inves-
tigation of alternative routes and some reactions of the
spirooxiranes 2 are reported in the present paper.
2c
–
2d
3-Cl,4-
MeOC6H3
–
3a
3b
3c
4a
4b
4c
4d
4e
4f
i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
i-Pr
Ph
Ph
Me
i-Pr
Ph
H
–
80
55
62
98
99
83
86
98
99
96
90
60
50
46
–
H
–
Me
H
–
H
Me
Et
i-Pr
H
Me
Et
i-Pr
–
H
H
Prior to our investigations, MCPBA had been applied
for the epoxidation of achiral 3-ylidenepyrazine-2,5-di-
ones.3–5 Thus 3,6-bis-ylidenepyrazine-2,5-diones could
be epoxidised by MCPBA.4 Remarkably, this reaction
stopped after the first epoxidation, i.e. a further epoxida-
tion of the resulting 3-ylidenepyrazine-2,5-dione moiety
H
Me
Me
Me
Me
PhCO
PhCO
H
did not occur. We also found the 3-ylidenepyrazine-2,5- 4g
diones 1 to be resistant to MCPBA. The more powerful
dimethyldioxirane, however, epoxidised 3-ylidenepyra-
4h
zine-2,5-diones 1 at room temperature (Scheme 1). The
resulting oxiranes 2 (Tables 1 and 2) could only be isolat-
ed if an electron-withdrawing acyl group (R2 = Ac or Bz)
was attached to the adjacent nitrogen atom. Otherwise
(R2 = H, Me) diols 3 were obtained, which were obviously
formed by hydrolytic ring-opening of the expected diox-
iranes 2 by traces of water found in the solution of the
5a
5b
–
5c
–
6
H
–
7a/8a
7b/8b
7c/8c
PhCO
PhCO
H
–
53
53
38
–
Synthesis 2003, No. 1, Print: 30 12 2002.
Art Id.1437-210X,E;2003,0,01,0067,0072,ftx,en;T07102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
–

68
A. Bartels et al.
PAPER
We also tried to synthesise epoxides 2 by intramolecular
nucleophilic substitution at bromohydrins 4 (R3 = H). The
bromohydroxylation and bromoalkoxylation of 1 with
NBS in the presence of water or alcohol, respectively, af-
forded excellent yields of adducts 4 (Scheme 1, Table 1).
The stereoselectivity, however, was low in particular in
the case of bromohydroxylation (R3 = H) where the at-
tacking water is less voluminous as compared with alco-
hols (R3 = alkyl) in bromoalkoxylations. As could be
proved by X-ray crystal analysis of compound 4f
(Figure 2), the attack of the bromine occurred preferably
from the same side as the epoxidation, i.e. anti with re-
spect to the trimethylene bridge between positions 1 and 6
of the pyrazine-2,5-dione ring of 1. Additions of bromine
and alkoxides to 3-ylidenepyrazine-2,5-diones had been
reported before, but achiral or racemic starting materials
were used and the stereochemical mode of addition could
not fully be determined.3–6 Attempts to convert 4a into the
corresponding oxirane 2 under basic conditions, as suc-
cessfully used in the 3,5-bisbenzylidenepyrazine-2,5-di-
one or in the racemic series,3,4 gave low yields and modest
stereoselectivity (70:30) and thus the intramolecular ox-
irane formation starting from 4 cannot compete with the
epoxidation of 1 with dimethyldioxirane.
Figure 2 X-ray crystal structure of compound 4f (radii are arbitrary)
Scheme 1
We further investigated the reduction of the oxirane ring
of the spiropyrazine-2,5-diones 2 in order to obtain 3-(1-
hydroxyethyl)pyrazine-2,5-diones 5 as precursors for -
amino- -hydroxycarboxylic acids such as allo-threonine
10 (Figure 1). As reported by Marcuccio et al.,4 Pd/C-ca-
talysed hydrogenation of oxiranes derived from 3,6-bis-
ylidenepyrazine-2,5-diones under basic conditions
opened the oxirane by maintaining the hemiaminal moi-
ety, i. e. by forming 3-benzyl-3-hydroxypyrazines. In con-
trast, hydrogenation of 2c with Pd/C at 30 atm in methanol
gave an epimeric mixture of the deacetylated ring-opened
products 5c and 6, while the hemiaminal structure was
erased and the acetyl group was split off. Epimers 5c and
6 could not be separated by column chromatography. In
order to achieve a more stereoselective transformation of
oxiranes 2 into 3-(1-hydroxyethyl)-pyrazine-2,5-diones 5,
we chose a detour applied by Marcuccio in the racemic
exhibit the same sign of optical rotation (Table 2). The
configuration at the hemiaminal carbon atom of diols 3 re-
mains unknown.
O
H
R2
NH2
N+
OH
R1
N
OH
O
OX
O
10
11
Figure 1 Structures of allo-threonine (10) and N-acyliminium salts
11
Synthesis 2003, No. 1, 67–72 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Addition Reactions with 3-Ylidenepyrazine-2,5-diones
69
series.4 At first, the oxirane ring of the spiro compounds 2 yl)pyrazine-2,5-dione (5a) was hydrolysed with 6 N aque-
was opened by refluxing in toluene in the presence of cat- ous HCl at 120 °C for 20 hours. As could be determined
alytic amounts of p-TsOH, followed by hydrogenation. by capillary GC-MS (L-Chirasil-Val), allo-threonine 10
Interestingly, mixtures of keto/enol forms 7 and 8 (see (Figure 1) was formed in 88% ee.
Table 2) were obtained after the first step, rather than just
ketones as found by Marcuccio. Conditions of hydrogena-
tion of 7/8 to 3-(1-hydroxyethyl)pyrazine-2,5-diones 5
(see Table 2) must be controlled since extended reaction
times gave rise to the formation of 3-alkylpyrazine-2,5-di-
ones 9, which are probably formed by elimination of wa-
ter from 5 to give 3-ylidenepyrazine-2,5-diones 1,
followed by further hydrogenation. The diastereomeric
ratios of the hydrogenation products 5 are high (Table 2).
The stereochemical outcome of the hydrogenation implies
that the keto form 7 rather than the enol 8 was reduced. At-
tack at the latter would have led to the opposite configura-
tions of the hydrogenation product. For proving the
absolute configuration, a sample of 3-(1-hydroxyeth-
In summary, epoxidation of the C–C double bond of 3-
ylidenepyrazine-2,5-diones 1 with dimethyldioxirane and
bromine/alcohol or bromine/water addition occur in the
same stereochemical mode providing spirooxiranes 2,
corresponding diols 3 or 3-(1-bromoalkyl)pyrazine-2,5-
diones 4, respectively. These products represent new op-
tically active and configurationally stable -keto acid de-
rivatives. Rearrangement and reduction of spirooxiranes 2
give access to the synthesis of optically active 3-(1-hy-
droxyalkyl)pyrazine-2,5-diones 5 as new derivatives of -
amino- -hydroxy acids.
Table 2 Spirooxiranes 2, Diols 3, 5-(1-Bromoalkyl)pyrazine-2,4-diones 4, Hydroxyalkylpyrazindiones 5, Acylpyrazindiones 7 and Enols 8
Prepared
Product dr
Mp (°C)
169–170
1H NMR (CDCl3) , J (Hz)
13C NMR (CDCl3)
2a
2b
>95:5a
1.20 (d, J = 5.8, 3 H, CH3), 1.91 (m, 2 H, CH2),
2.16–2.24 (m, 2 H, CH2), 3.48–3.53 (m, 2 H,
CH2N), 4.08 (q, J = 5.8, 1 H, CH), 4.56 (t, J = 7.7, (CH), 133.5 (C), 134.1 (CH), 161.7 (C), 170.2 (C),
1 H, 3-H) 7.39–7.74 (m, 5 H, C6H5)
15.2 (CH3), 23.4(CH2), 26.4 (CH2), 45.2 (CH2N),
58.9 (CH), 59.0 (CH), 71.3 (C), 128.6 (CH), 130.2
170.6 (C)
>95:5b
179–189
0.85 (d, J = 6.4, 3 H, CH3), 0.99 (d, J = 6.5, 3 H,
CH3), 1.90 (m, 1 H, CH), 2.15–2.23 (m, 4 H, 2
18.5 (CH3), 20.3 (CH3), 23.4 (CH2), 26.4 (CH),
27.9 (CH2), 45.2 (CH2N), 59.0 (CH), 67.4 (CH),
CH2), 3.50 (m, 2 H, CH2N), 3.62 (d, J = 5.9, 1 H, 73.0 (C), 128.6 (CH), 130.4 (CH), 133.4 (CH),
CHO), 4.55 (t, J = 7.7, 1 H, 6-H), 7.50–7.70 (m, 5 134.2 (C), 161.9 (C), 170.3 (C), 170.8 (C)
H, C6H5)
2c
>95:5c
>95:5d
137–138
150–154
1.90–1.94 (m, 2 H, CH2), 1.97 (s, 3 H, CH3), 2.21– 23.4 (CH2), 26.3 (CH3), 27.0 (CH2), 44.8 (CH2N),
2.35 (m, 2 H, CH2), 3.48 (m, 2 H, CH2N), 4.61 (t, 60.3 (CH), 62.7 (CH), 71.7 (C),126.6 (CH), 128.2
J = 7.9, 1 H, 6-H), 4.93 (s, 1 H, CH), 7.25 (s, 5 H, (CH), 128.9 (CH), 132.5 (C), 161.3 (C), 169.8 (C),
C6H5)
171.5 (C)
2d
1.95–2.01 (m, 2 H, CH2), 2.06 (s, 3 H, CH3), 2.27 20.6 (CH3), 23.5 (CH2), 26.5 (CH3), 27.1 (CH2),
(s, 3 H, CH3), 2.29–2.36 (m, 2 H, CH2), 3.47–3.53 45.0 (CH2N), 60.1 (CH), 61.7 (CH), 71.7 (C),
(m, 2 H, CH2N), 4.61 (t, J = 7.9, 1 H, 6-H), 4.93
(s, 1 H, CH), 7.01–7.20 (m, 3 Harom
123.7 (CH), 126.6 (CH), 127.1 (C),128.0 (CH),
131.9 (C), 147.4 (C), 160.9 (C), 168.2 (C), 169.9
(C), 171.3 (C)
)
3a
>95:5e
155–157
0.81 (d, J = 6.6, 3 H, CH3), 0.92 (d, J = 6.6, 3 H,
18.2 (CH3), 20.1 (CH3), 21.9 (CH2), 28.7 (CH2),
CH3), 1.82–1.92 (m, 2 H,CH2), 1.97 (m, 1 H, CH), 30.0 (CH), 45.4 (CH2N), 58.6 (CHN), 77.3
2.33–2.38 (m, 2 H, CH2), 3.38 (m, 2 H, CH2N),
4.22 (dd, 1J = 6.5, 2J = 10.2, 1 H, CHN), 5.57 (br,
1 H, OH), 5.85 (d, J = 10.4, 1 H, CHO)
(CHO), 83.0 (CO), 164.4 (C), 170.5 (C)
3b
3c
>90:10f
92:8
158
1.35–1.65 (m, 2 H, CH2), 1.82–2.32 (m, 2 H,
CH2), 3.21–3.33 (m, 2 H, CH2N), 3.65 (dd,
1J = 5.7, 2J = 11.3, 1 H, CHN), 5.38 (s, 1 H,
CHO), 7.19–7.29 (m, 5 H, C6H5)
20.7 (CH2), 28.5 (CH2), 44.9 (CH2N), 58.6
(CHN), 77.7 (CHO), 88.9 (CO), 127.8 (CH),
128.2 (CH), 128.7 (CH), 135.4 (C), 163.3 (C),
167.7 (C)
160–161.5 1.50 (m, 2 H, CH2), 1.84 (m, 2 H, CH2), 3.20 (s, 3 20.8 (CH2), 28.2 (CH2), 30.2 (CH3), 44.9 (CH2N),
H, CH3N), 3.42–3.53 (m, 2 H, CH2N), 3.70 (dd,
1J = 5.7, 2J = 11.8, 1 H, CHN), 5.32 (s, 1 H,
CHO), 6.00 (br, 1 H, OH), 7.23–7.28 (m, 5 H,
C6H5)
58.9 (CHN), 80.2 (CHO), 88.0 (CO), 127.0 (CH),
128.0 (CH), 128.6 (CH) 137.4 (C), 164.7 (C),
165.9 (C)
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70
A. Bartels et al.
PAPER
Table 2 Spirooxiranes 2, Diols 3, 5-(1-Bromoalkyl)pyrazine-2,4-diones 4, Hydroxyalkylpyrazindiones 5, Acylpyrazindiones 7 and Enols 8
Prepared (continued)
Product dr
Mp (°C)
148–150
1H NMR (CDCl3) , J (Hz)
13C NMR (CDCl3)
4a
4b
4c
58:42
1.03–2.02 (m, 4 H, 2 CH2), 3.15–3.42 (m, 2 H,
21.0 (CH2), 28.3 (CH2), 44.6 CH2N), 58.2 (CH),
60.4 (CH), 83.6 (C), 127.7 (CH), 128.4 (CH),
CH2N), 4.07 (dd, 1J = 6.3, 2J = 6.1, 1 H, H), 5.58
(s, 1 H, CH), 7.23–7.48 (m, 5 H, C6H5), 8.44 (s, 1 130.1 (CH), 136.9 (C), 162.1 (C), 168.2 (C)
H, NH)g
60:34:6
88:12
127–128
121–124
1.15 (m, 1 H, CH2), 1.35–2.14 (m, 3 H, CH2), 3.30 20.9 (CH2), 28.5 (CH2), 45.0 (CH2N), 51.9 (CH3),
(m, 2 H, CH2N), 3.37 (s, 3 H, OCH3), 3.89 (m, 1
H, 6-H), 5.54 (s, 1 H, CH), 7.27–7.45 (m, 5 H,
C6H5), 8.57(s, 1 H, NH)h
58.7 (CH), 59.4 (CH), 89.1 (C), 127.9 (CH), 128.9
(CH), 129.8 (CH), 135.0 (C), 159.8 (C), 167.5 (C)
0.71–0.81 (m, 1 H, CH2), 1.18 (t, J = 2.7, 3 H,
CH3), 1.42–2.07 (m, 3 H, CH2), 3.14–3.21 (m, 2
14.8 (CH3), 21.0 (CH2), 28.6 (CH2), 45.0 (CH2N),
58.8 (CH), 59.7 (CH), 60.3 (CH2O), 88.6 (C),
H, OCH2), 3.44 (dd, 1J = 7.1, 2J = 7.0, 1 H, CH2N), 128.0 (CH), 128.9 (CH), 129.9 (CH), 135.1 (C),
3.59 (dd, 1J= 7.1, 2J = 7.2, 1 H, CH2N), 3.90 (dd, 160.3 (C), 167.4 (C)
1J = 6.0, 2J = 6.1, 1 H, 6-H), 5.57 (s, 1 H, CH),
6.80 (s, 1 H, NH), 7.19–7.37 (m, 5 H, C6H5)
4d
79:12:9
116–119
1.08 (d, J = 6.2, 3 H, CH3), 1.12 (d, J = 6.1, 3 H,
20.6 (CH2), 23.0 (CH3), 23.1 CH3), 28.4 (CH2),
CH3), 1.04–2.00 (m, 4 H, 2 CH2), 3.11 (m, 2 H, 44.9 (CH2), 58.2 (CH), 60.0 (CH), 67.8 (CH), 88.6
CH2N), 3.85 (t, J = 6.1, 1 H, 6-H), 4.09 (m, 1 H,
OCH), 5.52 (s, 1 H, CH), 7.26–7.34 (m, 5 H,
C6H5), 8.55 (s, 1 H, NH)
(C), 127.8 (CH), 128.7 (CH), 130.1 (CH), 135.9
(C), 160.7 (C), 167.5 (C)
4e
4f
58:42
72:28
125–127
105–106
0.61 (m, 1 H, CH2), 1.61–1.69 (m, 2 H, CH2),
2.00–2.05 (m, 1 H, CH2), 2.69 (s, 3 H, CH3), 3.23 58.9 (CH), 59.0 (CH), 86.1 (C), 128.1(CH), 129.0
28.3 (CH2), 29.1 (CH3), 29.4 CH2), 44.7 (CH2N),
(m, 1 H, CH2N), 3.65 (m, 1 H, CH2N), 5.52 (s, 1
(CH), 129.6(CH), 134.8 (C), 162.8 (C), 165.7 (C)
H, CH), 7.28–7.43 (m, 5 H, C6H5)i
0.07–0.14 (m, 1 H, CH2), 1.23–1.57 (m, 2 H,
CH2), 1.76–1.89 (m, 1 H, CH2), 2.67 (s, 1 H,
CH3N), 3.24 (s, 3 H, CH3O), 3.33–3.56 (m, 2 H,
20.7 (CH2), 28.6 (CH2), 30.6 (CH3N), 45.4
(CH2N), 52.6 (OCH3), 57.5 (CH), 58.8 (CH),
91.9(C), 128.5 (CH), 129.2 (CH), 129.7 (CH),
CH2N), 3.76 (dd, 1J = 5.6, 2J = 5.8, 1 H, 6-H), 5.58 135.8 (C), 166.9 (C)
(s, 1 H, CH), 7.20–7.42 (m, 5 H, C6H5)j
4g
4h
5a
83:17
82:12
92:8
104–105
117–118
200–220
0.07 (m, 1 H, CH2), 1.24 (t, J = 7.0, 3 H, CH3),
1.38–1.51 (m, 2 H, CH2), 1.81–1.96 (m, 1 H,
CH2), 2.65 (s, 3 H, CH3N), 3.32–3.53 (m, 4 H,
14.5 (CH3), 20.5 (CH2), 28.4 (CH2), 30.5 (CH3N),
45.1 (CH2N), 57.5 (CH), 58.6 (CH), 60.8 (O CH2),
92.0 (C), 128.1 (CH), 128.8 (CH), 129.5 (CH),
CH2N, CH2O), 3.73 (dd, 1J = 5.7, 2J = 5.8, 1 H, 6- 135.7 (C), 160.7 (C), 166.6 (C)
H), 5.57 (s, 1 H, CH), 7.21–7.50 (m, 5 H, C6H5)
0.27 (m, 1 H, CH2), 1.12 (d, J = 4.6, 6 H, 2 CH3), 20.3 (CH2), 22.5 und 22.7 (CH3), 29.2 (CH2), 31.1
1.45–1.59 (m, 2 H, CH2), 1.87–2.07 (m, 1 H,
CH2), 2.62 (s, 3 H, CH3N), 3.18–3.30 (m, 2 H,
CH2N), 3.78 (m, 1 H, 6-H), 4.01 (m, 1 H, CH),
5.56 (s, 1 H, CH), 7.19–7.47 (m, 5 H, C6H5)
(CH3N), 45.1 (CH2N), 58.1 (CH), 58.2 (CH), 70.2
(CHO), 91.9 (C), 127.7 (CH), 128.4 (CH), 129.4
(CH), 135.5 (C), 160.7 (C), 166.2 (C)
1.36 (d, J = 6.4, 3 H, CH3), 1.84–2.06 (m, 2 H,
CH2), 2.30–2.47 (m, 2 H, CH2), 3.50–3.64 (m, 2
H, CH2N), 4.04–4.13 (m, 1 H, CH), 4.54 (t,
J = 2.3, 1 H), 5.89 (qd, qJ = 6.4, dJ = 3.1, 1 H,
CHO), 7.32–7.41 (m, 3 H, C6H5), 8.00–8.15 (m, 2
H, C6H5)
14.0 (CH3), 22.2 (CH2), 28.5 (CH2), 45.3 (CH2N),
58.1 (CH), 58.8 (CH), 70.2 (CHO), 128.3 (CH),
129.7 (C), 130.0 (CH), 133.2 (CH), 162.6 (C),
165.3 (C), 170.5 (C)
5b
5c
70:30
–
–
1.25 (d, J = 5.7, 3 H, CH3), 1.28 (d, J = 5.8, 3 H,
CH3), 1.84–1.97 (m, 3 H, CH, CH2), 2.16–2.19
(m, 2 H, CH2), 3.61–3.79 (m, 2 H, CH2N), 4.12
21.0 (2 CH3), 21.2 (CH2), 26.2 (CH), 32.0
(CH2), 47.7 (CH2N), 52.3 CH), 61.4 (CH), 68.6
(CHO), 126.2 (CH), 128.5 (CH), 129.8 (C), 130.3
(m, 1 H, CH), 4.59 (d, J = 4.2, 1 H, 3 H), 5.25 (dd, (CH), 133.7 (CH), 161.9 (C), 163.5 (C),171.2 (C)
1J = 2.9, 2J = 8.6, 1 H, CHO), 7.18–7.53 (m, 3 H,
C6H5), 7.86–7.95 (m, 2 H, C6H5)
>90:10
1.50–2.15 (m, 4 H, 2 CH2), 3.17–3.54 (m, 2 H,
CH2N), 4.23 (m, 1 H, CH), 4.38 (d, J = 8.0, 1 H,
21.3 (CH2), 28.6 (CH2), 44.8 (CH2N), 57.3 (CH),
59.0 (CH), 74.5 (CHO), 128.2 (CH), 128.5 (CH),
3-H), 5.18 (d, J = 8.0, 1 H, CHO), 7.18–7.50 (m, 5 129.9 (CH), 133.1 (C), 163.4 (C), 169.7 (C)
H, C6H5)
Synthesis 2003, No. 1, 67–72 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Addition Reactions with 3-Ylidenepyrazine-2,5-diones
71
Table 2 Spirooxiranes 2, Diols 3, 5-(1-Bromoalkyl)pyrazine-2,4-diones 4, Hydroxyalkylpyrazindiones 5, Acylpyrazindiones 7 and Enols 8
Prepared (continued)
Product dr
7a/8a
1:7k
Mp (°C)
80–81
1H NMR (CDCl3) , J (Hz)
13C NMR (CDCl3)
7a: 1.62–1.74 (m, 2 H, CH2), 1.84–1.93 (m, 2 H,
14.2 (CH3), 22.6 (CH2), 29.4 (CH2), 45.8 (CH2N),
60.1 (CH), 60.4 (CH3), 128.5 (CH), 128.9 (C),
CH2), 2.41 (s, 3 H, CH3), 3.46–3.89 (m, 2 H,
CH2N), 3.87 (dd, 1J = 6.6, 2J = 9.8, 1 H, CH), 5.47 130.4 (CH), 133.8 (CH), 159.0 (C), 163.4 (C),
(s, 1 H, 3-H), 7.41 (m, 3 H, CH), 8.03 (m, 2 H)
168.8 (C), 198.6 (C)
8a: 1.62–1.74 (m, 2 H, CH2), 1.84–1.93 (m, 2 H,
17.0 (CH3), 21.9 (CH2), 28.3 (CH2), 45.5 (CH2N),
58.7 (CH), 119.3 (C), 128.5 (CH), 128.9 (C),
CH2), 2.41 (s, 3 H, CH3), 3.46–3.89 (m, 2 H,
CH2N), 3.87 (dd, 1J = 6.6, 2J = 9.8, 1 H, CH), 7.41 130.4 (CH), 133.8 (CH), 141.5 (COH), 157.9 (C),
(m, 3 H, C6H5), 8.03 (m, 2 H, C6H5), 8.90 (s, 1 H, 163.4 (C), 166.7 (C)
OH)
7b/8b
2:3k
–
7b: 1.03 (d, J = 6.6, 3 H, CH3), 1.27 (d,
J = 7.1, 3 H, CH3), 1.58–2.28 (m, 5 H, 2 CH2,
CH), 3.34–3.55 (m, 2 H, CH2N), 3.98 (m, 1 H,
17.2 (CH3), 19.2 (CH3), 22.6 (CH2), 29.4 (CH2),
38.2 (CH), 45.9 (CH2), 60.0 CH, 68.6 (CH), 128.1
(CH), 128.6 (CH), 128.9 (C), 132.5 (CH), 159.3
CH), 5.61 (s, 1 H, 3-H), 7.27–7.54 (m, 3 H, C6H5), (C), 162.9 (C), 169.2 (C), 204.8 (C)
8.05 (m, 2 H, C6H5)
8b: 0.90 (d, J = 6.9, 3 H, CH3), 1.10 (d,
J = 6.8, 3 H, CH3), 1.58–2.28 (m, 5 H, 2 CH2,
CH), 3.34–3.55 (m, 2 H, CH2N), 3.98 (m, 1 H,
CH), 7.27–7.54 (m, 3 H, C6H5), 8.05 (m, 2 H,
C6H5), 9.20 (s, 1 H, OH)
18.9 (CH3), 20.6 (CH3), 22,6 (CH2), 28.1 (CH2),
29.1 (CH), 45.5 (CH2N), 58.3 (CH), 119.0 (C)
128.5 (CH), 128.9 (C), 130.4 (CH), 133.5 (CH),
148.4 (C), 158.1 (C), 162.9 (C), 167.8 (C)
7c/8cl
3:1k
–
7c: 1.69–2.11 (m, 4 H, 2 CH2),), 3.47–3.65 (m, 22.0 (CH2), 28.7 (CH2), 46.1 (CH2N), 58.9 (CH),
2 H, CH2N), 4.14 (m, 1 H, CH), 5.64 (d, J = 4.1, 1 64.0 (CH), 128.7 (CH), 130.0 (CH), 133.4 (C),
H, 3-CH), 7.24–7.68 (m, 5 H, C6H5)
134.5 (CH), 160.1 (C), 172.2 (C), 191.4 (C)
8c: 1.69–2.11 (m, 4 H, 2 CH2), 3.47–3.65 (m, 2 21.0 (CH2), 28.5 (CH2), 45.6 (CH2N),
H, CH2N), 4.14 (m, 1 H, CH), 7.24–7.68 (m, 5 H, 56.1 (CH), 119.5 (C), 128.6 (CH), 130.2 (CH),
C6H5)
132.2 (C), 134.5 (CH) 139.7 (C), 156.9 (C), 169.7
(C)
a [ ]546 –279.3 (c = 1, CHCl3).
b [ ]546 –247.3 (c = 1, CHCl3).
c [ ]546 –206.2 (c = 1, CHCl3).
d [ ]546 –68.3 (c = 1.35, CHCl3).
e [ ]546 –124.6 (c = 1, CHCl3).
f [ ]546 –62.4 (c = 0.7, CHCl3).
g Major isomer. Minor isomer: 1H NMR (DMSO-d6): = 1.03–2.02 (m, 4 H, 2 CH2), 3.31 (m, 2 H, CH2N), 4.19 (dd, 1 H, 6-H, 1J = 6.3
Hz, 2J = 6.5 Hz), 5.35 (s, 1 H, CH), 7.24–7.61 (m, 5 H, C6H5), 8.56 (s, 1 H, NH). 13C NMR (DMSO-d6): = 21.4 (CH2), 28.7 (CH2), 38.9
(CH2N), 59.1 (CH), 60.0 (CH), 84.3 (C), 128.0 (CH), 129.9 (CH), 130.5 (CH), 135.1 (C), 163.1 (C), 168.5 (C).
h Major isomer. Minor isomer: 1H NMR (DMSO-d6): = 1.15 (m, 1 H, CH2), 1.35–2.14 (m, 3 H, CH2), 3.22 (s, 3 H, OCH3), 3.30 (m, 2 H,
CH2), 4.10 (dd, 1 H, 6-H, 1J = 6.0 Hz, 2J = 6.0 Hz), 5.54 (s, 1 H, CH), 7.27–7.45 (m, 5 H, C6H5), 8.5 (s, 1 H, NH). 13C NMR (CDCl3):
= 21.4 (CH2), 28.5 (CH2), 44.7 (CH2N), 52.1 (CH3), 57.3 (CH), 59.3 (CH), 89.5 (C), 128.0 (CH), 128.3 (CH), 129.9 (CH), 133.6 (C), 161.5
(C), 168.0 (C).
i Major isomer. Minor isomer: 1H NMR (CDCl3): = 0.61 (m, 1 H, CH2), 1.61–1.69 (m, 2 H, CH2), 2.00–2.05 (m, 1 H, CH2), 2.88 (s, 3 H,
CH3), 3.23 (m, 1 H, CH2N), 3.65 (m, 1 H, CH2N), 5.40 (s, 1 H, CH), 7.28–7.43 (m, 5 H, C6H5). 13C NMR (CDCl3): = 28.2 (CH2), 29.4
(CH2), 30.3 CH3), 44.8 (CH2N), 57.8 (CH), 59.4 (CH), 87.1 (C), 128.1(CH), 128.9 (CH), 129.7 (CH), 135.5 (C), 162.8 (C), 165.7 (C).
j Major isomer. Minor isomer: 1H NMR (CDCl3): = 0.07–0.14 (m, 1 H, CH2), 1.23–1.57 (m, 2 H, CH2), 1.76–1.89 (m, 1 H, CH2), 2.54 (s,
3 H, CH3N), 3.19 (s, 3 H, CH3O), 3.33–3.56 (m, 2 H, CH2N), 3.97 (dd, 1 H, 6-H, 1J = 5.7 Hz, 2J = 5.8 Hz), 5.55 (s, 1 H, CH), 7.20–7.47
(m, 5 H, C6H5). 13C NMR (CDCl3): = 21.2 (CH2), 29.3 (CH3N), 29.6 (CH2), 45.8 (CH2N), 53.0 (OCH3), 57.6 (CH), 59.1 (CH), 92.4 (C),
127.9 (CH), 128.8 (CH), 130.6 (CH), 134.7 (C), 167.3 (C).
k Ratio of isomers 7:8, determined by NMR spectroscopy.
l Obtained from 2c.
Spirooxiranes 2 and Diols 3 by Epoxidation of 3-Ylidenepyra-
zine-2,5-diones 1; General Procedure
1H NMR and 13C NMR spectra were recorded at 300 and 75.5 MHz,
respectively, on a Bruker AC-300 with TMS as internal standard.
Mass spectra (HP 5995 A) were measured at 70 eV. Optical rota-
tions were determined with a Perkin-Elmer Polarimeter 241. Silica
gel (0.04–0.063 mm, Merck) was used for preparative column chro-
matography. If not otherwise mentioned, chemicals were purchased
from Aldrich. Starting materials 17 and solutions of dimethyldiox-
irane in acetone8 were obtained following literature procedures.
Anhyd MgSO4 (500 mg) and ca. 0.1 M solution of dimethyldiox-
irane in acetone (ca. 20 mL) were added to a solution of 3-
ylidenepyrazine-2,5-dione 1 (0.7 mmol for 2a, 0.26 mmol for 2b,
0.6 mmol for 2c, 0.82 mmol for 2d, 0.41 mmol for 3a, 0.33 mmol
for 3b, 0.78 mmol for 3c) in anhyd CH2Cl2 (20 mL). The mixture
was stirred under argon overnight. Eventually, (TLC check) addi-
tional dimethyldioxirane solution (5 mL portions) was added. After
all starting material had disappeared, the MgSO4 was filtered off
Synthesis 2003, No. 1, 67–72 ISSN 0039-7881 © Thieme Stuttgart · New York

72
A. Bartels et al.
PAPER
and the filtrate was submitted to column chromatography (2a:
EtOAc–hexane, 10:1, Rf 0.8; 2b: EtOAc–hexane, 6:1, Rf 0.8; 2c:
EtOAc–hexane, 10:1, Rf 0.7; 2d: EtOAc–hexane, 6:1, Rf 0.8; 3a:
CHCl3–MeOH, 6:1, Rf 0.4; 3b: CHCl3–MeOH, 6:1, Rf 0.5; 3c:
CHCl3–MeOH, 6:1, Rf 0.5). The products were purified by recrys-
tallisation.
the solvent was removed under vacuum. The remainder was dis-
solved in EtOAc (50 mL) and the resulting solution was washed
with H2O (3 20 mL) and brine (20 mL). The organic layer was
dried (Na2SO4) and the solvent was stripped off. The remaining sol-
id was purified by recrystallisation affording the product as colour-
less crystals.
Hydrolysis of Spirooxiranes 2 to 3-Acylpyrazine-2,5-diones 7
and Enols 8; General Procedure
X-Ray Crystal Analysis of 4f9
Crystal Data: Triclinic, space group P–1, a = 7.999(4),
A mixture of spirooxirane 2 (1.3 mmol), p-TsOH (22 mg, 0.13
mmol), MgSO4 (500 mg) and anhyd toluene (30 mL) was refluxed
for 1–3 h. The yellow colour of the solution disappeared as the re-
action came to completion. MgSO4 was filtered off and the filtrate
was washed with H2O (2 15 mL) and brine (15 mL). The organic
layer was dried (MgSO4), concentrated and submitted to column
chromatography (EtOAc–hexane, 10:1, Rf 0.45/0.40 for 7a/8a; 0.5
for 7b/8b; 0.5 for 7/8c). Products were obtained as isomeric mix-
tures which were submitted to reduction (see below).
b = 8.110(3), c = 12.567(5) Å,
= 105.27(3),
= 91.69(3),
= 101.34(3)°, V = 768.3 Å3, Z = 2, Dc = 1.588 Mg m–3,
F(000) = 376, = 2.7 mm–1, T = –100 °C. Data Collection: A crys-
tal of ca. 0.5 0.5 0.4 mm was used to register 4557 intensities
(Mo-K radiation, 2
55°) on a Stoe STADI-4 diffractometer.
max
Structure Refinement: The structure was refined anisotropically
against F2 (program SHELXL-97, G.M. Sheldrick, Univ. of Göttin-
gen) to wR2 = 0.088, R1 = 0.036 for 201 parameters and 3525 inde-
pendent reflections; max.
= 0.51 eÅ–3, S = 1.05. Hydrogen
atoms were included using a riding model or rigid methyl groups.
Hydrogenation of Spirooxirane 2b to 3-(2-Hydroxyethyl)pyra-
zine-2,5-diones 5c and 6
Acknowledgement
10% Pd/C (about 30 mg) was added to a solution of 2b (100 mg,
0.33 mmol) in anhyd MeOH (10 mL). The mixture was placed un-
der H2 at 30 atm for 14 h. After filtration through Celite, the solution
was concentrated and the remainder was purified by column chro-
matography (EtOAc–hexane 10:1, Rf 0.5) affording an epimeric
mixture of 5c and 6 (40 mg, 46%) as a colourless oil.
We acknowledge financial support by the Deutsche Forschungsge-
meinschaft (DFG) and the Fonds der Chemischen Industrie.
References
1H NMR (DMSO-d6): (major isomer) = 1.69–1.89 (m, 2 H, CH2),
(1) Liebscher, J.; Jin, S. Chem. Soc. Rev. 1999, 28, 251; and
references cited therein.
(2) Bartels, A.; Jones, P. G.; Liebscher, J. Tetrahedron Lett.
1995, 36, 3673.
(3) (a) Hoare, J. H.; Yates, P. J. Chem. Soc., Chem. Commun.
1981, 1126. (b) Yates, P.; Horare, J. H. Can. J. Chem. 1983,
61, 1397.
(4) Marcuccio, S. M.; Elix, J. A. Aust. J. Chem. 1985, 38, 1785.
(5) Itoh, K.; Kasami, M.; Yamada, R.; Kubo, T.; Honda, M.;
Serva, A. Heterocycles 1997, 45, 1345.
(6) (a) Marshall, J. A.; Schlaf, T. F.; Csernansky, J. G. Synth.
Commun. 1975, 5, 237. (b) Shin, C. G.; Sato, Y.; Honda, S.;
Yoshimura, J. Bull. Chem. Soc. Jpn. 1983, 56, 2652.
(c) Oh, Y. S.; Kohn, H. J. Org. Chem. 1992, 57, 3662.
(d) Moyroud, J.; Gelin, J.; Chéne, A.; Mortier, J.
Tetrahedron 1996, 52, 8525. (e) Gelin, J.; Mortier, J.;
Moyroud, J.; Chéne, A. J. Org. Chem. 1993, 58, 3473.
(f) Marcuccio, S. M.; Elix, J. A. Aust. J. Chem. 1985, 38,
343.
(7) Poisel, H.; Schmidt, U. Chem. Ber. 1973, 106, 3408.
(8) (a) Adam, W.; Hadjiarapoglou, L.; Smerz, A. Chem. Ber.
1991, 124, 277. (b) Messeguer, A.; Sánchez-Baeza, F.;
Casas, J.; Hammock, B. D. Tetrahedron 1991, 47, 1291.
(c) Nemes, C.; Lévai, A.; Patonay, T.; Toth, G.; Boros, S.;
Halász, J.; Adam, W.; Golsch, D. J. Org. Chem. 1994, 59,
900.
2.14–2.24 (m, 2 H, CH2), 3.30–3.59 (m, 2 H, CH2N), 3.91 (dd,
2
1J = 7.0 Hz, J = 9.1 Hz, 1 H, CH), 4.53 (t, J = 7.9 Hz, 1 H, CH),
5.31 (dd, 1J = 3.6 Hz, 2J = 9.2 Hz, 1 H, CHOH), 7.23–7.31 (m, 5 H,
C6H5).
13C NMR (DMSO-d6): (major isomer) = 22.7 (CH2), 27.7 (CH2),
44.8 (CH2N), 57.2 (CHN), 58.6 (CHN), 78.6 (CHOH), 127.1 (CH),
128.2 (CH), 129.5 (CH), 137.1 (C), 164.3 (C), 168.0 (C).
1H NMR (DMSO-d6): (minor isomer) = 1.69–1.89 (m, 2 H, CH2),
2.14–2.24 (m, 2 H, CH2), 3.30–3.59 (m, 2 H, CH2N), 4.23 (dd,
2
1J = 3.5 Hz, J = 8.2 Hz, 1 H, CH), 4.53 (t, J = 7.9 Hz, 1 H, CH),
4.96 (dd, 1J = 5.2 Hz, 2J = 7.9 Hz, 1 H, CHOH), 7.23–7.31 (m, 5 H,
C6H5).
13C NMR (DMSO-d6): (minor isomer) = 21.6 (CH2), 28.5 (CH2),
44.9 (CH2N), 55.8 (CHN), 58.6 (CHN), 81.2 (CHOH), 128.1 (CH),
128.5 (CH), 129.6 (CH), 135.5 (C), 163.4 (C), 168.0 (C)
Reduction of 3-Acylpyrazine-2,5-diones 7 and Enols 8 to 3-(1-
Hydroxyalkyl)pyrazine-2,5-diones 5; General Procedure
A mixture of Pd/C (ca. 30 mg), 7/8 (0.5 mmol) and anhyd MeOH
(20 mL) was hydrogenated at 15 atm. The resulting mixture was fil-
tered through Celite and the filtrate was submitted to column chro-
matography (EtOAc–hexane, 10:1, Rf 0.35 for 5a, 0.5 for 5b, 0.5
for 5c. In the case of 5a, the 3-alkyl product 9a (R1 = Me,
R2 = PhCO) was obtained as a byproduct in 40% yield.
(9) Complete crystallographic data (excluding structure factors)
have been deposited at the Cambridge Crystallographic Data
Centre under the number CCDC-187708. Copies can be
obtained free of charge from CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: Int. +44(1223)336033;
e-mail: deposit@ccdc.cam.ac.uk].
NBS Addition to 3-Ylidenepyrazine-2,5-diones 1; 3-(1-Bromo-
alkyl)pyrazine-2,5-diones 4; General Procedure
R3OH (2 mL) or H2O (2 mL) was added to a solution of 3-
ylidenepyrazine-2,5-dione 1 (3 mmol) in anhyd dioxane (20 mL). A
solution of NBS (0.534 g, 3 mmol) in anhyd dioxane (20 mL) was
slowly added under stirring. After the reaction had gone to comple-
tion (about 3 h, TLC check) and the yellow colour had disappeared,
Synthesis 2003, No. 1, 67–72 ISSN 0039-7881 © Thieme Stuttgart · New York