Microwave-assisted synthesis and functionalization of selenolopyrimidines

Article abstract of DOI:10.1055/s-0028-1088006

Microwave-assisted synthesis allowed efficient access to 4-chloroselenolo[3,2-d]pyrimidines in short times and very good yields. Some functionalizations by S_NAr and palladium-catalyzed reactions are also reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088006

1204
PAPER
Microwave-Assisted Synthesis and Functionalization of Selenolopyrimidines
M
icrowave-
A
t
ssiste
d
é
Synthesis
o
p
f
S
elenolopy
h
rimidines anie Hesse,* Célia Chenet, David Thomae, Gilbert Kirsch
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol FR CNRS 2843, Université Paul Verlaine-Metz,
1 Boulevard Arago, 57070 Metz, France
Fax +33(3)87315801; E-mail: hesse@univ-metz.fr
Received 20 November 2008; revised 26 November 2008
of microwave irradiation allowed shorter reaction times
Abstract: Microwave-assisted synthesis allowed efficient access to
and higher yields.
4-chloroselenolo[3,2-d]pyrimidines in short times and very good
yields. Some functionalizations by SNAr and palladium-catalyzed
reactions are also reported.
N
NH2
HCO2H
H2SO4
NH
Key words: selenium, pyrimidines, heterocycles, cyclizations,
microwave-assisted reactions
MW
10 min, 90 °C
R
R
CN
Se
2a–f
Se
O
1a–f
N
Heterocyclic condensed pyrimidines have attracted con-
siderable attention due to their interesting biological prop-
erties. For example, pyrrolo[2,3-d]pyrimidines1 and
pyrazolo[3,4-d]pyrimidines2 have been described as anti-
angiogenic agents, thieno[3,2-d]pyrimidines3 as antago-
nists of human adenosine A2 receptors, and furo[2,3-
d]pyrimidines4 as inhibitors of Lck. In contrast, studies of
selenolopyrimidines have been scarce.5
POCl3
MW
N
R
Se
20 min, 95 °C
Cl
3a–f
Scheme 1
Table 1 Microwave-Assisted Synthesis of Chloroselenolopyrim-
idines
Our laboratory has been interested in the synthesis of se-
lenophenes and selenolocondensed systems for many
years.6 We recently described the synthesis of sele-
nophene analogues of tacrine, starting from 3-aminosele-
nophene-2-carbonitriles,7 and thought that those starting
materials would also allow easy access to selenolopyrim-
idines, as we have previously done the same in the
thiophene series.8 This moiety is of interest, as 4-(alkyl-
amino)pyrimido[4¢,5¢:4,5]selenolo[2,3-b]quinolines were
reported to be antitumor agents9 and pyrimi-
do[4¢,5¢:4,5]selenolo[2,3-c]pyridazines were tested for
anti-inflammatory activity.10
R
Product 2 Yield (%) Product 3 Yield (%)
Ph
2a
2b
2c
2d
2e
2f
83
88
91
92
87
65
3a
3b
3c
3d
3e
3f
98
93
95
98
83
67
Tol
PMP
4-ClC6H4
4-O2NC6H4
t-Bu
3-Aminoselenophene-2-carbonitriles 1a–f were reacted
with formic acid in the presence of catalytic amounts of
sulfuric acid under microwave irradiation (Scheme 1). Se-
lenolo[3,2-d]pyrimidin-4-ones 2a–f were obtained in
good yields after only ten minutes of irradiation. Com-
pounds 2a, 2b, and 2f were also synthesized under classi-
cal heating (110 °C, 4 h) in yields of 77, 86, and 53%,
respectively. Compounds 2a–f were converted into 4-
chloroselenolo[3,2-d]pyrimidines 3a–f by reaction with
phosphoryl chloride. Reactions were also performed un-
der microwave irradiation for only 20 minutes at 95 °C
(Scheme 1, Table 1). Compound 3b was also prepared un-
der classical heating (90 °C, 18 h) in 71% yield. In both
cases, namely the syntheses of compounds 2 and 3, the use
Inspired by literature procedures,11 we also tested another
preparation of selenolo[3,2-d]pyrimidin-4-ones by the re-
action of 3-aminoselenophene-2-carboxamides with ethyl
oxalate. First, the cyano groups of compounds 1b, 1d, and
1f were converted into amides after ten minutes of micro-
wave irradiation in concentrated sulfuric acid (Scheme 2).
Compound 4b was also obtained under classical condi-
tions (20 °C, 15 h) in 75% yield.
NH2
NH2
H2SO4
NH2
R
R
CN
MW
10 min, 50 °C
Se
Se
O
1b,d,f
4b R = Tol 86%
4d R = 4-ClC6H4 89%
4f R = t-Bu 92%
Scheme 2
SYNTHESIS 2009, No. 7, pp 1204–1208
x
x
.
x
x
.2
0
0
9
Advanced online publication: 06.03.2009
DOI: 10.1055/s-0028-1088006; Art ID: Z25308SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Microwave-Assisted Synthesis of Selenolopyrimidines
1205
CO2Et
N
NH2
O
(CO2Et)2
NH2
NH
reflux, 18 h
Se
Se
O
4b
5b 58%
CO2Et
NHCOCO2Et
NH2
N
NH2
O
(CO2Et)2
NH
NH2
+
t-Bu
t-Bu
t-Bu
Se
reflux, 18 h
Se
5f 41%
Se
O
O
4f
5f′ 15%
Scheme 3
CO2Et
CO2Et
N
N
POCl3
95 °C, 16 h
NH
N
Se
Se
6 79%
O
Cl
5b
Scheme 4
N
N
NaOPMP
N
N
PMP
PMP
DMF, 90 °C, 2 h
Se
Se
3c
OPMP
Cl
7 45%
N
PMPB(OH)2
Pd(OAc)2, Ph3P, Cs2CO3
N
PMP
Se
N
PMP
EtOH–DME–H2O (1:1:1)
MW, 150 °C, 30 min
8 68%
N
HN
O
N
O
N
MW, 125 °C, 20 min
Se
9 86%
Cl
Se
3d
Cl
N
Cl
Scheme 5
Subsequent reaction of compound 4b with ethyl oxalate We next studied the reactivity of the chlorine atom of
led to selenolo[3,2-d]pyrimidin-4-one 5b in 58% yield af- some 4-chloroselenolopyrimidines in SNAr and palladi-
ter 18 hours of reflux (Scheme 3). The reaction mixture um-catalyzed reactions. Compound 3c was reacted with
was cooled to room temperature and diluted with cyclo- sodium 4-methoxyphenoxide in N,N-dimethylformamide,
hexane; compound 5b precipitated and was isolated by fil- and gave compound 7 in 45% yield (Scheme 5). Suzuki
tration. The same reaction was performed with compound coupling was performed under microwave irradiation and
4f (Scheme 3). After similar treatment, the non-cyclized gave compound 8 in good yield. Substitution by a second-
intermediate 5f¢ was isolated by filtration in 15% yield. ary aliphatic amine was also easy under microwave irradi-
Hydrolysis and extraction of the reaction mixture gave the ation, as compound 3d readily reacted with morpholine to
expected product 5f in 41% yield. Attempts were made to give compound 9 in 86% yield.
transpose this reaction under microwave irradiation, but it
was difficult to find the right conditions. Compound 5b
In conclusion, 3-aminoselenophene-2-carbonitriles are in-
teresting scaffolds and have allowed the synthesis of 18
was then submitted to chlorination, and product 6 was ob-
new selenolo[3,2-d]pyrimidines with diverse substituents.
tained in 79% yield (Scheme 4).
The syntheses we described here were achieved in very
short times thanks to the use of microwave irradiation.
Synthesis 2009, No. 7, 1204–1208 © Thieme Stuttgart · New York

1206
S. Hesse et al.
PAPER
13C NMR (62.5 MHz, DMSO-d6): d = 160.7, 158.0, 154.1, 147.4,
Moreover, this procedure is also attractive due to easy
workup (simple filtrations) and easy purification when
134.2, 133.3, 129.2, 128.2, 125.7, 124.8.
necessary (only recrystallization and no column chroma- ESI-HRMS: m/z [M + H]+ calcd for C12H8ClN2OSe: 310.9483;
found: 310.9465.
tography on silica gel).
6-(4-Nitrophenyl)selenolo[3,2-d]pyrimidin-4-one (2e)
Brown solid; mp 272 °C (dec).
IR (KBr): 3436, 1651 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 12.62 (br s, 1 H), 8.24–8.30
(m, 3 H), 8.21 (s, 1 H), 8.10 (d, J = 8.5 Hz, 2 H).
13C NMR (62.5 MHz, DMSO-d6): d = 160.5, 158.0, 152.3, 147.6,
147.5, 140.4, 127.6, 127.5, 127.3, 124.4.
ESI-HRMS: m/z [M + H]+ calcd for C12H8N3O3Se: 321.9725;
Melting points were determined on a Stuart SMP3 apparatus and are
1
uncorrected. H and 13C NMR spectra were recorded on an AC
Bruker 250-MHz spectrometer. HRMS was performed on a Bruker
MICROTOF-Q ESI/QqTOF spectrometer. IR spectra were record-
ed on a Perkin Elmer Spectrum BX spectrometer. A CEM Discover
microwave oven was used for the microwave-assisted reactions. 3-
Aminoselenophene-2-carbonitriles 1a–f were synthesized as previ-
ously reported.7
found: 321.9727.
Selenolopyrimidinones 2a–f; General Procedure
A 50-mL one-necked round-bottomed flask equipped with a stirrer
bar was charged with the appropriate 3-aminoselenophene-2-carbo-
nitrile 1 (2 mmol), HCO2H (99%, 4 mL), and concd H2SO4 (0.25
mL). The reaction mixture was placed in a microwave reactor
(CEM Discover) and was heated at 90 °C for 10 min. After cooling,
the mixture was poured into H2O and the precipitate was filtered.
The crude product was purified by recrystallization from EtOH.
6-tert-Butylselenolo[3,2-d]pyrimidin-4-one (2f)
Brown solid; mp 225 °C (dec).
IR (KBr): 3448, 1644 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 12.36 (br s, 1 H), 8.10 (s, 1 H),
7.34 (s, 1 H), 1.37 (s, 9 H).
13C NMR (62.5 MHz, DMSO-d6): d = 172.9.5, 160.2, 158.4, 146.8,
123.9, 122.9, 36.8, 32.0.
6-Phenylselenolo[3,2-d]pyrimidin-4-one (2a)
ESI-HRMS: m/z [M + H]+ calcd for C10H13N2OSe: 257.0188;
found: 257.0182.
Brown solid; mp 190 °C (dec).
IR (KBr): 3437, 1639 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 12.50 (br s, 1 H), 8.17 (s, 1 H),
7.99 (s, 1 H), 7.78 (d, J = 7.7 Hz, 2 H), 7.45–7.47 (m, 3 H).
13C NMR (62.5 MHz, DMSO-d6): d = 160.8, 158.0, 155.8, 147.3,
134.4, 129.6, 129.3, 126.4, 125.3, 124.0.
ESI-HRMS: m/z [M + H]+ calcd for C12H9N2OSe: 276.9875; found:
276.9884.
Chloroselenolopyrimidines 3a–f; General Procedure
A mixture of the appropriate selenolopyrimidinone 2 (1 mmol) and
POCl3 (8 mL) was heated at 95 °C for 20 min in a microwave reac-
tor. The excess POCl3 was removed by distillation under reduced
pressure. The residue was triturated with ice and H2O, and the solid
thus obtained was collected and recrystallized from EtOH.
4-Chloro-6-phenylselenolo[3,2-d]pyrimidine (3a)
Brown solid; mp 90 °C (dec).
1H NMR (250 MHz, DMSO-d6): d = 9.00 (s, 1 H), 8.35 (s, 1 H),
7.90–7.94 (m, 2 H), 7.44–7.53 (m, 3 H).
13C NMR (62.5 MHz, DMSO-d6): d = 159.6, 157.9, 156.2, 147.5,
134.3, 129.7, 129.3, 126.5, 125.3, 123.4.
ESI-HRMS: m/z [M + H]+ calcd for C12H8ClN2Se: 294.9533; found:
294.9532.
6-(4-Tolyl)selenolo[3,2-d]pyrimidin-4-one (2b)
Brown solid; mp 270 °C (dec).
IR (KBr): 1660 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 12.46 (br s, 1 H), 8.16 (s, 1 H),
7.94 (s, 1 H), 7.69 (d, J = 7.9 Hz, 2 H), 7.28 (d, J = 7.9 Hz, 2 H),
2.33 (s, 3 H).
13C NMR (62.5 MHz, DMSO-d6): d = 160.9, 158.0, 156.0, 147.2,
139.5, 131.7, 129.8, 126.3, 124.8, 123.3, 20.8.
ESI-HRMS: m/z [M + H]+ calcd for C13H11N2OSe: 291.0031;
found: 291.0023.
4-Chloro-6-(4-tolyl)selenolo[3,2-d]pyrimidine (3b)
Brown solid; mp 310 °C (dec).
1H NMR (250 MHz, DMSO-d6): d = 8.98 (s, 1 H), 8.28 (s, 1 H),
7.81 (d, J = 8.1 Hz, 2 H), 7.33 (d, J = 8.1 Hz, 2 H), 2.36 (s, 3 H).
13C NMR (62.5 MHz, DMSO-d6): d = 165.6, 159.5, 155.5, 155.2,
141.0, 131.5, 130.8, 130.0, 127.0, 122.4, 20.9.
ESI-HRMS: m/z [M + H]+ calcd for C13H10ClN2Se: 308.9690;
found: 308.9681.
6-(4-Methoxyphenyl)selenolo[3,2-d]pyrimidin-4-one (2c)
Brown solid; mp 260 °C (dec).
IR (KBr): 3436, 1683 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 8.14 (s, 1 H), 7.85 (s, 1 H),
7.74 (d, J = 8.8 Hz, 2 H), 7.02 (d, J = 8.8 Hz, 2 H), 3.80 (s, 3 H).
13C NMR (62.5 MHz, DMSO-d6): d = 161.1, 160.4, 158.0, 155.8,
147.2, 128.0, 127.0, 123.5, 122.5, 114.6, 55.4.
ESI-HRMS: m/z [M + H]+ calcd for C13H11N2O2Se: 306.9980;
4-Chloro-6-(4-methoxyphenyl)selenolo[3,2-d]pyrimidine (3c)
Brown solid; mp 160 °C (dec).
1H NMR (250 MHz, DMSO-d6): d = 8.96 (s, 1 H), 8.21 (s, 1 H),
7.88 (d, J = 8.8 Hz, 2 H), 7.07 (d, J = 8.8 Hz, 2 H), 3.83 (s, 3 H).
13C NMR (62.5 MHz, DMSO-d6): d = 165.8, 161.4, 159.4, 155.3,
155.2, 131.1, 128.8, 126.1, 121.4, 114.8, 55.5.
ESI-HRMS: m/z [M + H]+ calcd for C13H10ClN2OSe: 324.9641;
found: 324.9650.
found: 306.9984.
6-(4-Chlorophenyl)selenolo[3,2-d]pyrimidin-4-one (2d)
Brown solid; mp 235 °C (dec).
IR (KBr): 3402, 1673 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 12.50 (br s, 1 H), 8.18 (s, 1 H),
8.04 (s, 1 H), 7.83 (d, J = 8.6 Hz, 2 H), 7.53 (d, J = 8.6 Hz, 2 H).
Synthesis 2009, No. 7, 1204–1208 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Synthesis of Selenolopyrimidines
1207
4-Chloro-6-(4-chlorophenyl)selenolo[3,2-d]pyrimidine (3d)
Brown solid; mp 125 °C (dec).
3-Amino-5-tert-butylselenophene-2-carboxamide (4f)
Brown solid; mp 105 °C (dec).
1H NMR (250 MHz, DMSO-d6): d = 9.02 (s, 1 H), 8.40 (s, 1 H),
7.96 (d, J = 8.5 Hz, 2 H), 7.59 (d, J = 8.5 Hz, 2 H).
13C NMR (62.5 MHz, DMSO-d6): d = 160.3, 158.0, 152.4, 147.6,
147.5, 140.4, 127.6, 127.5, 127.2, 124.4.
IR (KBr): 3485, 3448, 3327, 1634 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.58 (s, 1 H), 5.77 (br s, 2 H), 5.10
(br s, 2 H), 1.34 (s, 9 H).
13C NMR (62.5 MHz, DMSO-d6): d = 168.3, 167.3, 155.06, 120.0,
99.3, 36.6, 32.2.
ESI-HRMS: m/z [M + H]+ calcd for C12H7Cl2N2Se: 328.9146;
found: 328.9148.
ESI-HRMS: m/z [M + H]+ calcd for C9H15N2OSe: 247.0344; found:
247.0355.
4-Chloro-6-(4-nitrophenyl)selenolo[3,2-d]pyrimidine (3e)
Brown solid; mp 180 °C (dec).
1H NMR (250 MHz, DMSO-d6): d = 9.06 (s, 1 H), 8.58 (s, 1 H),
8.17–8.32 (m, 4 H).
13C NMR (62.5 MHz, DMSO-d6): d = 160.9, 160.4, 158.0, 155.9,
147.2, 127.9, 127.0, 124.2, 122.4, 114.6.
ESI-HRMS: m/z [M + H]+ calcd for C12H7ClN3O2Se: 339.9384;
found: 339.9381.
Ethyl Selenolo[3,2-d]pyrimidine-2-carboxylates 5; General
Procedure
The appropriate 3-amino-selenophene-2-carboxamide 4 was dis-
solved in diethyl oxalate (3 mL/mmol) and the reaction mixture was
refluxed for 18 h. After cooling, the mixture was concentrated under
reduced pressure and diluted with cyclohexane. The precipitate was
filtered.
Ethyl 6-(4-Tolyl)selenolo[3,2-d]-4-oxopyrimidin-2-carboxylate
(5b)
Brown solid; mp 205 °C (dec).
IR (KBr): 3427, 1752, 1651 cm–1.
1H NMR (250 MHz, CDCl3): d = 9.96 (br s, 1 H), 7.88 (s, 1 H), 7.52
(d, J = 7.6 Hz, 2 H), 7.28 (d, J = 7.6 Hz, 2 H), 4.58 (q, J = 7.1 Hz, 2
H), 2.41 (s, 3 H), 1.50 (t, J = 7.1 Hz, 3 H).
13C NMR (62.5 MHz, CDCl3): d = 160.6, 159.8, 159.3, 157.6,
143.8, 140.3, 132.0, 130.0, 129.0, 126.6, 123.5, 64.2, 21.3, 14.2.
6-tert-Butyl-4-chloroselenolo[3,2-d]pyrimidine (3f)
Compound 3f was isolated by extraction of the reaction mixture
with CH2Cl2; the organic layers were dried (MgSO4), filtered, and
concentrated under reduced pressure.
Brown solid; mp 68–70 °C.
1H NMR (250 MHz, CDCl3): d = 8.88 (s, 1 H), 7.48 (s, 1 H), 1.47
(s, 9 H).
13C NMR (62.5 MHz, CDCl3): d = 176.9, 165.2, 156.5, 154.7,
132.2, 122.2, 37.6, 32.5.
ESI-HRMS: m/z [M + H]+ calcd for C10H12ClN2Se: 274.9846;
found: 274.9845.
ESI-HRMS: m/z [M + H]+ calcd for C16H15N2O3Se: 363.0242;
found: 363.0243.
Ethyl 6-tert-Butylselenolo[3,2-d]-4-oxopyrimidin-2-carboxy-
late (5f)
Brown solid; mp 130–132 °C (dec).
Conversion of Nitriles 1b,d,f into Amides 4b,d,f; General Proce-
dure
The appropriate 3-aminoselenophene-2-carbonitrile 3 was dis-
solved in H2SO4 (1 mL/mmol) and the reaction mixture was irradi-
ated at 50 °C for 10 min in a CEM Discover microwave oven. The
reaction mixture was poured onto H2O and neutralized with sat. aq
Na2CO3. The precipitate was filtered.
IR (KBr): 1739, 1651 cm–1.
1H NMR (250 MHz, CDCl3): d = 10.50 (br s, 1 H), 7.52 (s, 1 H),
4.56 (q, J = 7.2 Hz, 2 H), 1.41–1.51 (m, 12 H).
13C NMR (62.5 MHz, CDCl3): d = 175.7, 160.6, 159.23, 157.8,
143.5, 128.3, 123.4, 64.1, 37.4, 32.5, 14.2.
3-Amino-5-(4-tolyl)selenophene-2-carboxamide (4b)
Brown solid; mp 238 °C (dec).
IR (KBr): 3455, 3339, 3298, 3153, 1640 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C13H17N2O3Se: 329.0399;
found: 329.0392.
1H NMR (250 MHz, DMSO-d6): d = 7.40 (d, J = 7.6 Hz, 2 H), 7.21
(d, J = 7.6 Hz, 2 H), 7.14 (s, 1 H), 6.79 (br s, 2 H), 6.63 (br s, 2 H),
2.29 (s, 3 H).
Ethyl {[2-(Aminocarbonyl)-5-tert-butylselenophen-3-yl]ami-
no}(oxo)acetate (5f¢)
Brown solid; mp 214–215 °C (dec).
13C NMR (62.5 MHz, DMSO-d6): d = 167.6, 155.6, 148.6, 138.3,
IR (KBr): 3390,3336, 3259, 3167, 1727, 1697, 1663 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 12.75 (br s, 1 H), 8.11 (s, 1 H),
7.59 (br s, 2 H), 4.27 (q, J = 7.1 Hz, 2 H), 1.38–1.26 (m, 12 H).
132.3, 129.7, 125.5, 120.3, 100.3, 20.7.
ESI-HRMS: m/z [M + H]+ calcd for C12H13N2OSe: 281.0188;
found: 281.0191.
13C NMR (62.5 MHz, DMSO-d6): d = 168.2, 166.6, 159.6, 152.8,
142.1, 119.0, 116.2, 62.7, 36.4, 32.1, 13.7.
3-Amino-5-(4-chlorophenyl)selenophene-2-carboxamide (4d)
Brown solid; mp 195 °C (dec).
IR (KBr): 3368, 3272, 3165, 1662 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C13H19N2O4Se: 347.0505;
found: 347.0528.
1H NMR (250 MHz, DMSO-d6): d = 7.3 (d, J = 8.6 Hz, 2 H), 7.46
(d, J = 8.6 Hz, 2 H), 7.22 (s, 1 H), 6.85 (br s, 2 H), 6.66 (br s, 2 H).
Ethyl 4-Chloro-6-(4-Tolyl)selenolo[3,2-d]pyrimidin-2-carboxy-
late (6)
A mixture of selenolopyrimidinone 3c (1 mmol) and POCl3 (8 mL)
was charged in a round-bottom flask and heated at 95 °C for 16 h.
The excess POCl3 was removed by distillation under reduced pres-
sure. The residue was triturated with ice and H2O, and the solid thus
obtained was collected by filtration.
13C NMR (62.5 MHz, DMSO-d6): d = 167.5, 155.4, 146.8, 133.9,
133.1, 129.2, 127.3, 121.6, 101.4.
ESI-HRMS: m/z [M + H]+ calcd for C11H10ClN2OSe: 300.9641;
found: 300.9644.
Brown solid; mp 135–136 °C (dec).
Synthesis 2009, No. 7, 1204–1208 © Thieme Stuttgart · New York

1208
S. Hesse et al.
PAPER
IR (KBr): 1740 cm–1.
Brown solid; mp >300 °C.
1H NMR (250 MHz, CDCl3): d = 8.06 (s, 1 H), 7.59 (d, J = 7.9 Hz,
2 H), 7.31 (d, J = 7.9 Hz, 2 H), 4.59 (q, J = 7.1 Hz, 2 H), 2.44 (s, 3
H), 1.49 (t, J = 7.1 Hz, 3 H).
1H NMR (250 MHz, acetone-d6): d = 8.51 (s, 1 H), 7.92 (s, 1 H),
7.84 (d, J = 8.5 Hz, 2 H), 7.54 (d, J = 8.5 Hz, 2 H), 3.89–391 (m, 4
H), 3.81–3.83 (m, 4 H).
13C NMR (62.5 MHz, CDCl3): d = 165.8, 163.1, 161.4, 156.9,
153.7, 141.6, 135.0, 133.1, 130.2, 127.1, 122.5, 63.0, 21.5, 14.3.
13C NMR (62.5 MHz, acetone-d6): d = 166.5, 160.9, 165.6, 152.9,
135.9, 134.3, 130.3, 129.1, 125.6, 116.4, 67.2, 47.1.
ESI-HRMS: m/z [M + H]+ calcd for C16H14ClN2O2Se: 380.9902;
ESI-HRMS: m/z [M + H]+ calcd for C16H15ClN3OSe: 380.0061;
found: 380.9895.
found: 380.0064.
4-(4-Methoxyphenoxy)-6-(4-methoxyphenyl)selenolo[3,2-d]py-
rimidine (7)
Acknowledgment
A 10-mL round-bottom flask was charged with compound 3c (0.5
mmol), NaOPMP (1 mmol) and DMF (2.5 mL). The reaction mix-
ture was heated at 90 °C for 2 h. After cooling, the mixture was
poured onto H2O and the precipitate was filtered.
We thank Marion Thevenin for her participation in this project du-
ring her training course in our laboratory.
References
Yellow solid; mp 170 °C (dec).
1H NMR (250 MHz, DMSO-d6): d = 8.64 (s, 1 H), 8.10 (s, 1 H),
7.83 (d, J = 8.7 Hz, 2 H), 7.27 (d, J = 9 Hz, 2 H), 7.06 (d, J = 8.7 Hz,
2 H), 7.00 (d, J = 9 Hz, 2 H), 3.82 (s, 3 H), 3.78 (s, 3 H).
13C NMR (62.5 MHz, DMSO-d6): d = 166.8, 165.1, 160.9, 157.2,
157.0, 154.9, 145.1, 128.4, 126.6, 122.9, 121.2, 116.8, 114.8, 114.6,
55.44, 55.42.
(1) Gangjee, A.; Namjoshi, O. A.; Yu, J.; Ihnat, M. A.; Thorpe,
J. E.; Warnke, L. A. Bioorg. Med. Chem. 2008, 16, 5514.
(2) Ducray, R.; Ballard, P.; Barlaam, B. C.; Hickinson, M. D.;
Kettle, J. G.; Ogilvie, D. J.; Trigwell, C. B. Bioorg. Med.
Chem. Lett. 2008, 18, 959.
(3) Gillespie, R. J.; Adams, D. R.; Bebbington, D.; Benwell, K.;
Cliffe, I. A.; Dawson, C. E.; Dourish, C. T.; Fletcher, A.;
Gaur, S.; Giles, P.; Jordan, A. M.; Knight, A. R.; Knutsen, L.
J. S.; Lawrence, A.; Lerpiniere, J.; Misra, A.; Porter, R. H.
P.; Pratt, R. M.; Shepherd, R.; Upton, R.; Ward, S. E.; Weiss,
S. M.; Williamson, D. S. Bioorg. Med. Chem. Lett. 2008, 18,
2916.
(4) DiMauro, E. F.; Newcomb, J.; Nunes, J. J.; Bemis, J. E.;
Boucher, C.; Buchanan, J. L.; Buckner, W. H.; Cheng, A.;
Faust, T.; Hsieh, F.; Huang, X.; Lee, J. H.; Marshall, T. L.;
Martin, M. W.; McGowan, D. C.; Schneider, S.; Turci, S.
M.; White, R. D.; Zhu, X. Bioorg. Med. Chem. Lett. 2007,
17, 2305.
(5) (a) Litivinov, V. P.; Mortikov, V. Y. Synthesis 1985, 98.
(b) Nandeeshaiah, S. K.; Ambekar, S. Y. Synth. Commun.
1995, 25, 451. (c) Abdel-Hafez, Sh. H. Russ. J. Org. Chem.
2005, 41, 396. (d) Abdel-Hafez, Sh. H.; Abdel-Mohsen, S.
H.; El-Ossailly, Y. A. Phosphorus, Sulfur Silicon Relat.
Elem. 2006, 181, 2297.
ESI-HRMS: m/z [M + H]+ calcd for C20H17N2O3Se: 413.0400;
found: 413.0409.
4,6-Bis(4-methoxyphenyl)selenolo[3,2-d]pyrimidine (8)
A 50-mL round-bottomed flask was charged with compound 3c (1
mmol), PMPB(OH)2 (1.5 mmol), Cs2CO3 (3.1 mmol), PPh3 (5
mol%), Pd(OAc)2 (2.5 mol%), and DME–EtOH–H2O (1:1:1, 30
mL), and flushed with argon. The reaction mixture was placed in a
microwave synthesizer. The microwave vial was purged three
times with argon and then heated under microwave irradiation
(150 °C) for 30 min. The mixture was subsequently allowed to cool
to r.t. and was quenched with EtOAc–H2O (1:1, 20 mL). The aque-
ous layer was extracted with EtOAc (3 × 30 mL). The combined or-
ganic layers were washed with brine and dried (MgSO4). The
solvent was removed under reduced pressure. The residue was pu-
rified by column chromatography (silica gel, EtOAc); this gave
product 8.
(6) (a) Sommen, G.; Comel, A.; Kirsch, G. Synlett 2003, 855.
(b) Sommen, G.; Comel, A.; Kirsch, G. Synthesis 2004, 451.
(7) Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2008, 1600.
(8) Hesse, S.; Perspicace, E.; Kirsch, G. Tetrahedron Lett. 2007,
48, 5261.
(9) (a) Gopal, M.; Veeranna, S.; Doddamani, L. S. Spectrosc.
Lett. 2004, 37, 347. (b) Gopal, M.; Veeranna, S.
J. Photochem. Photobiol., B 2005, 81, 181.
Pale yellow solid; mp 169 °C.
1H NMR (250 MHz, DMSO-d6): d = 9.14 (s, 1 H), 8.15–8.08 (m, 3
H), 7.89–7.83 (d, J = 8.8 Hz, 2 H), 7.20 (d, J = 8.8 Hz, 2 H), 7.07
(d, J = 8.8 Hz, 2 H), 3.87 (s, 3 H), 3.83 (s, 3 H).
13C NMR (62.5 MHz, DMSO-d6): d = 165.8, 161.5, 161.0, 159.7,
157.6, 155.4, 129.9, 129.4, 128.5, 128.0, 126.4, 121.5, 114.8, 114.6,
55.44, 55.42.
(10) Abdel-Hafez, Sh. H. Eur. J. Med. Chem. 2008, 9, 1971.
(11) (a) Mason, J. J.; Bergman, J. Org. Biomol. Chem. 2007, 5,
2486. (b) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. J. Org. Chem.
2007, 72, 6270; and references cited therein.
6-(4-Chlorophenyl)-4-morpholinoselenolo[3,2-d]pyrimidine (9)
Compound 3d (0.5 mmol) was dissolved in excess morpholine (4
mL). The reaction mixture was heated at 125 °C for 20 min under
microwave irradiation. After cooling, the mixture was poured onto
H2O and the precipitate was filtered.
Synthesis 2009, No. 7, 1204–1208 © Thieme Stuttgart · New York