Mn(OAc)3-mediated selective free radical phosphonylation of pyridinones and pyrimidinones

Article abstract of DOI:10.1055/s-0033-1338423

The phosphonyl radical generated from the reaction of dimethyl phosphite with manganese(III) acetate adds selectively to the 3-position of pyridin-2-ones or the 5-position of pyrimidin-4-ones to afford phosphonylated products in good yields. Georg Thieme

Full text of DOI:10.1055/s-0033-1338423

PAPER
▌1529
paper
Mn(OAc)3-Mediated Selective Free Radical Phosphonylation of Pyridinones
and Pyrimidinones
Mn(OAc) -Mediated Selective Free Radical Phosphonylation
a
a
a
a
Wang-Bin Sun, Yun-Fei Ji, Xiang-Qiang Pan, Shao-Fang Zhou, Jian-Ping Zou,*a,b Wei Zhang,*c
3
Olayinkataiwo Asekund
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University,
199 Renai Street, Suzhou, Jiangsu 215123, P. R. of China
Fax +86(512)65880335; E-mail: jpzou@suda.edu.cn
b
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Ling Ling Road 345, Shanghai 200032, P. R. of China
c
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA
Fax +1(617)2876030; E-mail: wei2.zhang@umb.edu
d
Department of Chemistry, University of Lagos, Akoka, Yaba, Nigeria
Received: 27.01.2013; Accepted after revision: 26.03.2013
nese(III) acetate in three portions gave the best results.
Abstract: The phosphonyl radical generated from the reaction of
The reaction at 80 °C for 120 minutes afforded phospho-
dimethyl phosphite with manganese(III) acetate adds selectively to
nylated product 3a in 72% yield (Scheme 1).
the 3-position of pyridin-2-ones or the 5-position of pyrimidin-4-
ones to afford phosphonylated products in good yields.
O
Key words: manganese(III) acetate, phosphonylation, pyridinone,
pyrimidinone, dialkyl phosphite, free radical
HN
O
Phosphonylated azaheterocycles such as pyridinones and
PO(OMe)2
Mn(OAc)3
AcOH
1a
HN
pyrimidinones are associated with many biological active
compounds and are important in organic, medicinal, and
agricultural chemistry. Methods for the synthesis of py-
rimidinylphosphonates include direct reaction of dichlo-
ropyrimidine with triethyl phosphite,1 lithium 2,2,6,6-
tetramethylpiperidide promoted rearrangement,2 nucleo-
philic substitution,3 lithium–halogen exchange followed
by phosphonylation.4 Oxidative diphosphonylation has
been developed for 1,4-dihydropyridines and pyridinium
salts.5
+
80 °C, 2 h
HPO(OMe)2
2
3a
Scheme 1 Phosphonylation of 4,6-diphenylpyridin-2(1H)-one
A series of 4,6-disubstituted pyridinones were employed
to study the scope of this reaction. The results shown in
Table 1 indicated that in all the cases 3-phosphonylated
pyridinones were produced in moderate to good yields,
and no 5-phosphonylated pyridinones or phenyl phospho-
nylated products were observed. It was found that aromat-
ic substituents at the 4- and 6-positions of the pyridinone
have no significant effect on the product yield. Pyridinone
with methyl substitution at position 6 also produced the
desired product (Table 1, entry 9).
Manganese(III) acetate is a useful reagent in radical reac-
tions. The Ishii group reported the first catalytic phospho-
nation of arenes with dialkyl phosphites using
manganese(III) acetate/cobalt(II) acetate/oxygen as a re-
dox couple.6 We have recently reported mangangese(III)-
promoted selective phosphonation of aryl,7 heteroaryl,8
and conjugated alkene systems.9 This paper introduces
first examples of manganese(III) acetate promoted direct
phosphonation of pyridinones and pyrimidinones with a
dialkyl phosphite.10
The proposed mechanism for the phosphonylation of pyr-
idinones is shown in Scheme 2. Electrophilic phosphonyl
radical 6 generated from the reaction of manganese(III)
acetate with dimethyl phosphite attacks the 3-position of
pyridinones 1 to form radical 7 because this position has
higher electron density than other sites.10b Radical 7 is ox-
idized by the second equivalent of manganese(III) acetate
to form carbocation 8 followed by the deprotonation to
give product 3.
4,6-Diphenylpyridin-2(1H)-one (1a) was used as a sub-
strate for the development of reaction conditions. After
screening the reaction solvent, reagent ratio, reaction tem-
perature, and time, it was found that acetic acid was a
good solvent and the suitable reagent ratio was 1a/dimeth-
yl phosphite/manganese(III) acetate 1:2:3. It was also
found that the addition of three equivalents of manga-
Pyrimidinone is a privileged ring that exists in many nat-
ural products and synthetic medicines. There are a wide
variety of pharmacological properties and potential appli-
cations of pyrimidin-2(1H)-ones.11–14 They could be suit-
able substrates for phosphonylation. Indeed, the reaction
SYNTHESIS 2013, 45, 1529–1533
Advanced online publication: 29.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338423; Art ID: SS-2013-M0082-OP
© Georg Thieme Verlag Stuttgart · New York

1530
W.-B. Sun et al.
PAPER
Table 2 Phosphonylation of Pyrimidinones 4a
Table 1 Phosphonylation of Pyridinones 1a
O
O
N
O
O
Mn(OAc)3
PO(OMe)2
R2
PO(OMe)2
R2
Mn(OAc)3
HN
R1
HN
R1
AcOH
HN
R1
HN
R1
AcOH
+
HPO(OMe)2
+
HPO(OMe)2
N
R2
2
80 °C, 2 h
R2
80 °C, 2 h
2
4a–h
5a–h
1a–i
3a–i
Entry
Substrate R1
R2
Ph
Product Yieldb (%)
Entry Substrate R1
R2
Product Yieldb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
Me
5a
5b
5c
5d
5e
5f
65
67
70
69
75
70
65
68
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
3a
3b
3c
3d
72
68
62
69
66
70
63
60
55
Me
Me
Me
Ph
4-MeOC6H4
4-BrC6H4
4-ClC6H4
Ph
4-MeC6H4
4-MeOC6H4 Ph
4-BrC6H4
Ph
Ph
4-MeOC6H4 3e
4-BrC6H4 3f
Ph
4-MeC6H4
3-MeOC6H4
4-BrC6H4
Ph
4g
4h
Ph
5g
5h
1g
1h
1i
4-BrC6H4
Ph
4-MeOC6H4 3g
2-MeOC6H4 3h
Ph
a Method: 4/dimethyl phosphite/Mn(OAc)3 (1:2:3), AcOH (5 mL),
Me
Ph
3i
80 °C, 2 h under air.
a Method: 1/dimethyl phosphite/Mn(OAc)3 (1:2:3), AcOH (5 mL),
b Isolated yield.
80 °C, 2 h under air.
b Isolated yield.
In summary, we have developed a manganese(III)-medi-
ated regioselective phosphonation reaction of pyridinones
and pyrimidinones. The reactions are straightforward and
efficient. This reaction extended further the synthetic util-
ity of free-radical-based phosphonation of heterocyclic
ring systems in the synthesis of biologically interesting
compounds.
of pyrimidinone 4a with dimethyl phosphite afforded 5-
phosphonylated pyrimidinone 5a in 65% yield (Scheme
3). A series of substituted pyrimidinones were used for
phosphonylation. Results shown in Table 2 indicate that
substituents on the phenyl ring or at the 2-position of the
pyrimidinone have no significant effect on product yields.
The phosphonylation reaction was further extended to
other substrates. The reaction of pyrimidinedione 6a af-
forded 5-phosphonylated product 7a in 60% yield (Table
3, entry 1). Phosphonylation of 6-bromoquinolinone 6b
gave 3-phosphonylated product 7b in 78% yield (Table 3,
entry 2). Finally, direct phosphonylation was also applied
to the reaction of triacetyl uridine 6c to give the expected
product 7c in 70% yield (Table 3, entry 3). A multistep
synthesis is required to make this kind of compound fol-
lowing reported procedures.4
O
N
O
N
PO(OMe)2
Mn(OAc)3
AcOH
HN
HN
+ HPO(OMe)2
80 °C, 2 h
2
4a
5a
Scheme 3 Phosphonylation of pyrimidinone
O
O
O
PO(OMe)2
Ar
PO(OMe)2
Ar
Mn(III)
HN
HN
HN
+
•
Mn(II)
R
R
R
Ar
7
8
1a–i
•
PO(OMe)2
6
H+
Mn(OAc)3
HPO(OMe)2
O
PO(OMe)2
Ar
HN
2
R
3a–i
Scheme 2 Proposed mechanism for phosphonylation of pyridinones
Synthesis 2013, 45, 1529–1533
© Georg Thieme Verlag Stuttgart · New York

PAPER
Mn(OAc)3-Mediated Selective Free Radical Phosphonylation
1531
1H NMR (400 MHz, CDCl3): δ = 13.07 (s, 1 H, NH), 7.83 (d, J =
7.3 Hz, 2 H, ArH), 7.47–7.35 (m, 3 H, ArH), 7.25 (d, J = 7.7 Hz, 2
H, ArH), 7.15 (d, J = 7.8 Hz, 2 H, ArH), 6.55 (s, 1 H, CH), 3.35 (d,
J = 11.4 Hz, 6 H, 2 CH3), 2.31 (s, 3 H, CH3).
Table 3 Phosphonylation of Other Azaheterocycles 6a
Entry Substrate
Product
Yieldb
(%)
13C NMR (75 MHz, CDCl3): δ = 165.90 (d, JPC = 12.4 Hz), 162.26,
150.90, 138.76, 137.51 (d, JPC = 4.3 Hz), 133.30, 131.04, 129.44,
128.79, 127.99, 127.56, 110.10, 53.05 (d, JPC = 5.9 Hz), 21.57.
O
O
PO(OMe)2
HN
HN
HRMS (EI): m/z [M]+ calcd for C20H20NO4P: 369.1130; found:
1
60
78
369.1128 (69%).
O
N
O
N
H
H
Dimethyl 6-(4-Methoxyphenyl)-2-oxo-4-phenyl-1,2-dihydro-
pyridin-3-ylphosphonate (3c)
White solid; yield: 0.24 g (62%); mp 178–180 °C.
6a
7a
Br
Br
PO(OEt)2
1H NMR (400 MHz, CDCl3): δ = 12.80 (s, 1 H, NH), 7.93 (d, J =
8.0 Hz, 2 H, ArH), 7.32–7.46 (m, 5 H, ArH), 7.03 (d, J = 8.0 Hz, 2
H, ArH), 6.56 (s, 1 H, CH), 3.84 (s, 3 H, CH3), 3.43 (d, J = 11.3 Hz,
6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 165.84 (d, JPC = 12.6 Hz), 162.41
(d, JPC = 6.8 Hz), 162.17, 150.46, 140.68 (d, JPC = 4.1 Hz), 129.27,
128.70, 128.11, 127.95, 124.96, 114.89, 108.71 (d, JPC = 13.2 Hz),
55.75, 53.02 (d, JPC = 6.0 Hz).
2
3
N
O
N
O
H
H
7b
6b
O
N
O
N
(MeO)2OP
NH
NH
HRMS (EI): m/z [M]+ calcd for C20H20NO5P: 385.1079; found:
385.1075 (60%).
O
O
AcO
AcO
70
O
O
Dimethyl 6-(4-Bromophenyl)-2-oxo-4-phenyl-1,2-dihydropyri-
din-3-ylphosphonate (3d)
OAc OAc
OAc OAc
Yellow solid; yield: 0.30 g (69%); mp 188–190 °C.
6c
7c
1H NMR (400 MHz, CDCl3): δ = 13.21 (s, 1 H, NH), 7.96 (d, J =
7.2 Hz, 2 H, ArH), 7.59–7.48 (m, 5 H, ArH), 7.35 (d, J = 8.0 Hz, 2
H, ArH), 6.63 (s, 1 H, CH), 3.46 (d, J = 11.4 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 165.89 (d, JPC = 12.3 Hz), 161.12,
151.72, 139.49 (d, JPC = 4.5 Hz), 133.21, 131.50, 129.84, 129.72,
127.79, 123.31, 109.83, 53.32 (d, JPC = 5.8 Hz).
a Method: 6/dimethyl phosphite/Mn(OAc)3 (1:2:3), AcOH (5 mL), 80
°C, 2 h under air.
b Isolated yield.
All reactions were carried out under air. Solvents were dried by the
standard procedures. 1H and 13C NMR spectra were determined in
CDCl3 on a Varian-Inova 300 MHz or 400 MHz spectrometer and
relative to internal TMS. HRMS were recorded on a MicroMass-
TOF machine (EI). Column chromatography was performed with
200–300 mesh silica gel using flash column technique. All of the re-
agents were used directly as obtained commercially unless other-
wise noted.
HRMS (EI): m/z [M]+ calcd for C19H17BrNO4P: 433.0079; found:
433.0070 (100%).
Dimethyl 4-(4-Methoxyphenyl)-2-oxo-6-phenyl-1,2-dihydro-
pyridin-3-ylphosphonate (3e)
Yellow solid; yield: 0.25 g (66%); mp 196–198 °C.
1H NMR (400 MHz, CDCl3): δ = 12.80 (s, 1 H, NH), 7.90 (d, J =
6.6 Hz, 2 H, ArH), 7.59–7.48 (m, 3 H, ArH), 7.41 (d, J = 7.6 Hz, 2
H, ArH), 6.96 (d, J = 7.6 Hz, 2 H, ArH), 6.65 (s, 1 H, CH), 3.86 (s,
3 H, CH3), 3.48 (d, J = 11.3 Hz, 6 H, 2 CH3).
Dimethyl 2-Oxo-4,6-diphenyl-1,2-dihydropyridin-3-ylphospho-
nate (3a); Typical Procedure
To a mixture of pyridinone 1a (0.25 g, 1.0 mmol), dimethyl phos-
phite (0.22 g, 2.0 mmol), and AcOH (5 mL) was added Mn(OAc)3·2
H2O (0.81 g, 3.0 mmol) in 3 portions; each portion was added when
the red color of soln had faded. The resulting soln was heated at 80
°C for 2 h. To the resulting mixture was added H2O (30 mL) and it
was extracted with EtOAc (3 × 10 mL). The combined organic lay-
ers were dried (anhyd Na2SO4) and concentrated in vacuo. The res-
idue was purified by column chromatography (acetone–petroleum
ether 2:1) to afford 3a as a yellow solid; yield: 0.26 g (72%); mp
174–176 °C.
1H NMR (400 MHz, CDCl3): δ = 12.54 (s, 1 H, NH), 7.90 (d, J =
6.3 Hz, 2 H, ArH), 7.55–7.35 (m, 8 H, ArH), 6.70 (s, 1 H, CH), 3.44
(d, J = 11.2 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 168.03, 164.65 (d, JPC = 4.1 Hz),
152.80, 142.75, 135.03, 133.40, 131.72, 131.00, 130.38, 130.17,
129.86, 111.82 (d, JPC = 12.8 Hz), 55.35.
13C NMR (75 MHz, CDCl3): δ = 161.93, 160.09, 150.57, 135.17,
132.84, 132.36, 130.90, 129.42, 129.21, 127.27, 113.32, 109.93,
55.32, 52.88.
HRMS (EI): m/z [M]+ calcd for C20H20NO5P: 385.1079; found:
385.1075 (60%).
Dimethyl 4-(4-Bromophenyl)-2-oxo-6-phenyl-1,2-dihydropyri-
din-3-ylphosphonate (3f)
White solid; yield: 0.30 g (70%); mp 184–186 °C.
1H NMR (400 MHz, CDCl3): δ = 12.66 (s, 1 H, NH), 7.93 (d, J =
6.7 Hz, 2 H, ArH), 7.50–7.57 (m, 5 H, ArH), 7.32 (d, J =7.7 Hz, 2
H, ArH), 6.59 (s, 1 H, CH), 3.47 (d, J = 11.0 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 162.69, 152.68, 140.83, 134.25,
132.80, 131.13, 131.04, 129.08, 124.60, 110.92, 54.61 (d, JPC = 5.4
Hz).
HRMS (EI): m/z [M]+ calcd for C19H17BrNO4P: 433.0079; found:
433.0080 (100%).
HRMS (EI): m/z [M]+ calcd for C19H18NO4P: 355.0973; found:
355.0974 (77%).
Dimethyl 6-(4-Bromophenyl)-4-(4-methoxyphenyl)-2-oxo-1,2-
dihydropyridin-3-ylphosphonate (3g)
Yellow solid; yield: 0.29 g (63%); mp 194–196 °C.
Dimethyl 2-Oxo-6-phenyl-4-p-tolyl-1,2-dihydropyridin-3-
ylphosphonate (3b)
Yellow solid; yield: 0.25 g (68%); mp 164–166 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1529–1533

1532
W.-B. Sun et al.
PAPER
1H NMR (400 MHz, CDCl3): δ = 13.27 (s, 1 H, NH), 7.86 (d, J =
8.0 Hz, 2 H, ArH), 7.67 (d, J = 7.9 Hz, 2 H, ArH), 7.39 (d, J = 8.1
Hz, 2 H, ArH), 6.97 (d, J = 8.1 Hz, 2 H, ArH), 6.71 (s, 1 H, CH),
3.87 (s, 3 H, OCH3), 3.50 (d, J = 11.3 Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 166.26, 161.70, 160.34, 132.62,
132.34, 129.63, 129.14, 125.72, 113.56, 110.74, 55.57, 53.07 (d, JPC
= 5.6 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C14H18N2O5P: 324.0875;
found: 325.0944.
Dimethyl 4-(4-Bromophenyl)-2-methyl-6-oxo-1,6-dihydropy-
rimidin-5-ylphosphonate (5c)
White solid; yield: 0.26 g (70%); mp 212–214 °C.
1H NMR (400 MHz, CDCl3): δ = 13.16 (br s, 1 H), 7.55 (d, J = 8.1
Hz, 2 H), 7.52 (d, J = 8.4 Hz, 2 H), 3.60 (d, J = 11.4 Hz, 6 H), 2.51
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.9 (d, J = 8.6 Hz), 164.6, 161.7,
138.0, 131.2, 130.8, 124.9, 109.8 (d, J = 200.5 Hz), 53.5 (d, J = 6.0
Hz), 22.0.
HRMS (EI): m/z [M]+ calcd for C20H19BrNO5P: 463.0184; found:
463.0185 (55%).
Dimethyl 4-(2-Methoxyphenyl)-2-oxo-6-phenyl-1,2-dihydro-
pyridin-3-ylphosphonate (3h)
Yellow solid; yield: 0.23 g (60%); mp 168–170 °C.
HRMS (ESI): m/z [M + H]+ calcd for C13H15BrN2O4P: 371.9876;
1H NMR (400 MHz, CDCl3): δ = 13.36 (s, 1 H, NH), 7.95 (d, J =
7.3 Hz, 2 H, ArH), 7.55–7.45 (m, 3 H, ArH), 7.37 (t, J = 7.6 Hz, 1
H, ArH), 7.22 (d, J = 7.1 Hz, 1 H, ArH), 7.02 (t, J = 7.3 Hz, 1 H,
ArH), 6.95 (d, J = 8.2 Hz, 1 H, ArH), 6.59 (s, 1 H, CH), 3.81 (s, 3
H, OCH3), 3.51 (d, J = 11.4 Hz, 3 H, CH3), 3.43 (d, J = 11.3 Hz, 3
H, CH3).
13C NMR (75 MHz, CDCl3): δ = 165.75 (d, JPC = 11.7 Hz), 162.90,
159.21, 156.05, 150.78, 133.18, 130.88, 130.01, 129.36, 127.62,
120.28, 110.63, 55.69, 52.97 (d, JPC = 28.5 Hz).
found: 372.9960.
Dimethyl 4-(4-Chlorophenyl)-2-methyl-6-oxo-1,6-dihydropy-
rimidin-5-ylphosphonate (5d)
White solid; yield: 0.23 g (69%); mp 219–220 °C.
1H NMR (400 MHz, CDCl3): δ = 13.3 (br s, 1 H), 7.59 (d, J = 8.2
Hz, 2 H), 7.38 (d, J = 8.2 Hz, 2 H), 3.60 (d, J = 11.0 Hz, 6 H), 2.49
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.0 (d, J = 6.1 Hz), 161.5, 137.7,
136.4, 130.6, 128.2, 53.4 (d, J = 4.6 Hz), 22.1.
HRMS (EI): m/z [M]+ calcd for C20H20NO5P: 385.1079; found:
385.1082 (15%).
HRMS (ESI): m/z [M + H]+ calcd for C13H15ClN2O4P: 328.0380;
found: 328.0460.
Dimethyl 6-Methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-
ylphosphonate (3i)
Dimethyl 6-Oxo-2,4-diphenyl-1,6-dihydropyrimidin-5-ylphos-
phonate (5e)
White solid; yield: 0.27 g (75%); mp 195–197 °C.
1H NMR (400 MHz, CDCl3): δ = 13.6 (br s, 1 H), 8.31–8.55 (m, 2
H), 7.71–7.84 (m, 2 H), 7.35–7.62 (m, 6 H), 3.51 (d, J = 11.1 Hz, 6
Yellow solid; yield: 0.16 g (55%); mp 190–192 °C.
1H NMR (400 MHz, CDCl3): δ = 13.64 (s, 1 H, NH), 7.40 (s, 5 H,
ArH), 6.08 (s, 1 H, CH), 3.53 (d, J = 11.0 Hz, 6 H, 2 CH3), 2.42 (s,
3 H, CH3).
H).
13C NMR (75 MHz, CDCl3): δ = 165.75, 162.78, 149.67, 140.44,
128.63, 128.04, 127.82, 110.47 (d, JPC = 13.5 Hz), 53.00 (d, JPC
5.2 Hz), 19.42.
=
13C NMR (75 MHz, CDCl3): δ = 172.4 (d, J = 8.7 Hz), 158.2, 139.6,
133.2, 131.3, 130.4, 129.6, 129.3, 128.9, 127.9, 53.3 (d, J = 4.6 Hz).
HRMS (EI): m/z [M]+ calcd for C14H16NO4P: 293.0817; found:
HRMS (ESI): m/z [M + H]+ calcd for C18H18N2O4P: 356.0926;
293.0816 (100%).
found: 357.1014.
Dimethyl 2-Methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-5-
ylphosphonate (5a); Typical Procedure
Dimethyl 6-Oxo-2-phenyl-4-p-tolyl-1,6-dihydropyrimidin-5-
ylphosphonate (5f)
To a mixture of pyrimidinone 4a (0.19 g, 1.0 mmol), dimethyl phos-
phite (0.22 g, 2.0 mmol), and AcOH (5.0 mL) was added
Mn(OAc)3·2 H2O (0.81 g, 3.0 mmol) in 3 portions and the resulting
soln was heated at 80 °C for 2 h. To the resulting mixture was added
H2O (30.0 mL) and it was extracted with EtOAc (3 × 10.0 mL). The
combined organic layers were dried (anhyd Na2SO4) and concen-
trated in vacuo. The residue was purified by column chromatogra-
phy (acetone–petroleum, 2:1) to afford 5a as a white solid; yield:
0.19 g (65%); mp 191–192 °C.
White solid; yield: 0.26 g (70%); mp 189–190 °C.
1H NMR (400 MHz, CDCl3): δ = 13.63 (br s, 1 H), 8.44 (d, J = 7.3
Hz, 2 H), 7.73 (d, J = 7.8 Hz, 2 H), 7.54–7.57 (m, 3 H), 7.27 (d, J =
7.9 Hz, 2 H), 3.55 (d, J = 11.4 Hz, 6 H), 2.42 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 172.6 (d, J = 8.0 Hz), 158.2, 141.1,
136.9, 133.4, 131.6, 131.6, 130.0, 129.5, 129.1, 128.9, 53.5 (d, J =
6.1 Hz), 22.0.
HRMS (ESI): m/z [M + H]+ calcd for C19H20N2O4P: 370.1082;
1H NMR (400 MHz, CDCl3): δ = 13.4 (br s, 1 H), 7.61–7.68 (m, 2
H), 7.41–7.47 (m, 3 H), 3.56 (d, J = 10.1 Hz, 6 H), 2.56 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 172.7 (d, J = 5.0 Hz), 161.7, 139.6,
130.7, 129.5, 128.5, 53.8 (d, J = 2.9 Hz), 22.6.
found: 371.1157.
Dimethyl 4-(3-Methoxyphenyl)-6-oxo-2-phenyl-1,6-dihydropy-
rimidin-5-ylphosphonate (5g)
White solid; yield: 0.25 g (65%); mp 192–193 °C.
HRMS (ESI): m/z [M + H]+ calcd for C13H16N2O4P: 294.0769;
found: 295.0842.
1H NMR (400 MHz, CDCl3): δ = 13.65 (br s, 1 H), 8.44 (d, J = 7.6
Hz, 2 H), 7.54–7.62 (m, 3 H), 7.35–7.41 (m, 3 H), 7.01–7.06 (m, 1
H), 3.88 (s, 3 H), 3.55 (d, J = 11.4 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 172.1 (d, J = 8.6 Hz), 159.2, 140.8,
133.3, 131.8 (d, J = 9.4 Hz), 129.3, 129.2, 129.1, 129.1 (d, J =176.2
Hz), 128.9, 122.0, 116.8, 114.5, 110.0, 55.7, 53.5 (d, J = 6.1 Hz).
Dimethyl 4-(4-Methoxyphenyl)-2-methyl-6-oxo-1,6-dihydropy-
rimidin-5-ylphosphonate (5b)
White solid; yield: 0.22 g (67%); mp 189–191 °C.
1H NMR (400 MHz, CDCl3): δ = 13.30 (br s, 1 H), 7.65 (d, J = 8.6
Hz, 2 H), 6.90 (d, J = 8.6 Hz, 2 H), 3.79 (s, 3 H), 3.55 (d, J = 11.4
Hz, 6 H), 2.47 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C19H20N2O5P: 386.1032;
found: 387.1103.
13C NMR (75 MHz, CDCl3): δ = 172.1 (d, J = 8.0 Hz), 165.7, 162.0,
161.0, 131.8, 131.7, 113.7, 108.7 (d, J = 201.7 Hz), 55.9, 53.6 (d,
J = 6.1 Hz), 22.4.
Dimethyl 4-(4-Bromophenyl)-6-oxo-2-phenyl-1,6-dihydropy-
rimidin-5-ylphosphonate (5h)
White solid; yield: 0.30 g (68%); mp 240–241 °C.
Synthesis 2013, 45, 1529–1533
© Georg Thieme Verlag Stuttgart · New York

PAPER
Mn(OAc)3-Mediated Selective Free Radical Phosphonylation
1533
1H NMR (400 MHz, CDCl3): δ = 13.45 (br s, 1 H), 8.31–8.51 (m, 2
H), 7.50–7.71 (m, 7 H), 3.57 (d, J = 14.0 Hz, 6 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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HRMS (ESI): m/z [M + H]+ calcd for C18H17BrN2O4P: 434.0031;
found: 435.0105.
References
Dimethyl 2,4-Dioxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-
ylphosphonate (7a)
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(10) Reviews on P–C bond formation by radical ractions: (a) Van
der Jeught, S.; Stevens, C. V. Chem. Rev. 2009, 109, 2672.
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White solid; yield: 0.18 g (60%); mp 210–213 °C.
1H NMR (400 MHz, CDCl3): δ = 8.39 (s, 1 H, NH), 8.16 (s, 1 H,
NH), 7.46–7.57 (m, 5 H), 3.55 (d, J = 10.7 Hz, 6 H).
HRMS (ESI): m/z [M + H]+ calcd for C12H14N2O5P: 296.0562;
found: 297.0635.
Diethyl 6-Bromo-2-oxo-1,2-dihydroquinolin-3-ylphosphonate
(7b)
Yellow powder; yield: 0.28 g (78%); mp 120–122 °C.
1H NMR (400 MHz, CDCl3): δ = 11.68 (br s, 1 H, NH), 8.48 (d, J =
17.4 Hz, 1 H, ArH), 7.81 (s, 1 H, ArH), 7.67 (d, J = 8.7 Hz, 1 H,
ArH), 7.27 (s, 1 H, CH), 4.50–4.10 (m, 4 H, 2 CH2), 1.40 (t, J = 6.7
Hz, 6 H, 2 CH3).
13C NMR (75 MHz, CDCl3): δ = 163.10, 150.01, 140.19, 136.71,
132.19, 122.31, 121.13, 120.92, 118.96, 116.54, 64.12 (d, JPC = 5.8
Hz), 17.48 (d, JPC = 6.3 Hz).
HRMS (EI): m/z [M]+ calcd for C13H15BrNO4P: 358.9922; found:
358.9922.
Dimethyl 2,4-Dioxo-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-
1,2,3,4-tetrahydropyrimidin-5-ylphosphonate (7c)4
Yellow oil; yield: 0.34 g (70%).
1H NMR (400 MHz, CDCl3): δ = 10.36 (br, 1 H, NH), 8.25 (d, J =
13.5 Hz, 1 H), 5.95 (d, J = 5.1 Hz, 1 H), 5.43–5.38 (m, 1 H), 5.36–
5.33 (m, 1 H), 4.33–4.29 (m, 3 H), 3.78 (d, J = 2.4 Hz, 3 H, OCH3),
3.75 (d, J = 2.4 Hz, 3 H, OCH3), 2.08 (s, 3 H, CH3), 2.05 (s, 3 H,
CH3), 2.01 (s, 3 H, CH3).
(11) Atwal, K. S.; Rovnyak, G. C.; Schwartz, J.; Moreland, S.;
Hedberg, A.; Gougoutas, J. Z.; Malley, M. F.; David, M. F.
J. Med. Chem. 1990, 33, 1510.
(12) Yamaguchi, M.; Wakasugi, K.; Saito, R.; Adachi, Y.;
Yoshikawa, Y.; Sakurai, H.; Katoh, A. J. Inorg. Biochem.
2006, 100, 260.
Acknowledgement
(13) Sadanandam, Y. S.; Shetty, M. M.; Diwan, P. V. Eur. J.
Med. Chem. 1992, 27, 87.
(14) Wright, C. M.; Chovatiya, R. J.; Jameson, N. E.; Turner, D.
M.; Zhu, G.; Werner, S.; Huryn, D. M.; Pipas, J. M.; Day, B.
W.; Wipf, P.; Brodskya, J. L. Bioorg. Med. Chem. 2008, 16,
3291.
J.P.Z. thanks the National Natural Science Foundation of China for
financial support (No. 20772088, 21172163) and A Project Funded
by the Priority Academic Program Development of Jiangsu Higher
Education Institutions.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1529–1533