Direct metal-free O-arylation of Biginelli 4-aryl-6-methyl-pyrimidine-2(1H)-one derivatives using diaryliodonium salts

Article abstract of DOI:10.1016/j.tetlet.2014.08.079

4-Aryl-6-methyl-pyrimidine-2(1H)-one scaffolds of Biginelli type were subjected to C-O cross-coupling reactions using symmetrical diaryliodonium salts under transition metal-free conditions to afford 2-aryloxy pyrimidine derivatives in good to excellent y

Full text of DOI:10.1016/j.tetlet.2014.08.079

Tetrahedron Letters 55 (2014) 5718–5721
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct metal-free O-arylation of Biginelli 4-aryl-6-methyl-
pyrimidine-2(1H)-one derivatives using diaryliodonium salts
⇑
Prerana B. Thorat, Nitin A. Waghmode, Nandkishor N. Karade
Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur 440 033, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Aryl-6-methyl-pyrimidine-2(1H)-one scaffolds of Biginelli type were subjected to C–O cross-coupling
reactions using symmetrical diaryliodonium salts under transition metal-free conditions to afford 2-aryl-
oxy pyrimidine derivatives in good to excellent yields.
Received 3 May 2014
Revised 20 August 2014
Accepted 22 August 2014
Available online 29 August 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Biginelli reaction
4-Aryl-6-methyl-pyrimidine-2(1H)-one
Heteroaryl ether
C–O cross-coupling
Diaryliodonium salts
In the last two decades, Biginelli 3,4-dihydropyrimidin-2(1H)-
one (DHPM) scaffolds have received considerable attention due
to a wide range of pharmaceutical properties such as antibacterial,
antitumor, anti-inflammatory, calcium channel blockers, antihy-
OMe
N
OMe
N
OMe
N
F
Cl
N
MeO
N
O
O
OMe MeO
HO
N
O
pertensive agents,
ala-antagonists, and neuropeptide Y (NPY)
COONa
O
antagonists.1 In addition, several marine alkaloids containing the
dihydropyrimidinone-5-carboxylate motifs also showed interest-
ing biological properties.2 Owing to these pharmacological proper-
ties, there is a growing interest to make post-modification of
DHPM scaffolds furnish ‘drug like’ small molecules for biological
screening.3 For example, the C2 position of DHPMs has been mod-
ified by the introduction of a wide range of N, O, and C-nucleo-
philes to form 2-substituted pyrimidine derivatives.4 The
pyrimidin-2(1H)-one derivative, obtained by the oxidative dehy-
drogenation of DHPMs, is generally a necessary intermediate for
the introduction of nucleophilic species at 2-position.5 In particu-
lar, the introduction of oxygen nucleophile at 2-position of Biginelli
DHPMs furnishes 2-aryloxy pyrimidine derivatives. Apart from
Biginelli pyrimidin-2(1H)-one derivatives, other cyclic amides such
as quinazolin-4(3H)-one6 and pyridin-2(1H)-one7 have also
received a considerable attention for the O-arylation at 2-position
to form heteroaryl ethers which are also found to be the sub-struc-
tural unit of various pharmaceuticals, herbicides, and functional
materials (Fig. 1).8
anti-inflammatory
Me
bispyribac sodium: Herbicide
N
H
N
Me
HN
O
O
F
F
N
N
Cl
N
Me
N
H
N
H
Me
(CRF) antagonist
PDE10A inhibitors
Figure 1. Examples of biologically active molecules that have heteroaryl ether core
structure
2(1H)-ones using TsCl, Ac2O, and POCl3 followed by aromatic
nucleophilic substitution (SNAr) with electron deficient phenolic
compounds (Scheme 1).9 However, this two-step strategy results
in low yields of 2-heteroaryl ether and requires harsh condition
during chlorination using POCl3 at high temperatures. Some of
the drawbacks of SNAr process for 2-heteroaryl ether synthesis
have been overcome by the oxidative Pd-catalyzed C–O cross-cou-
pling reaction of pyridotriazol-l-yloxypyrimidines with arylboronic
acids in the presence of dioxygen.10 Recently, the Mitsunobu reac-
tion of 2-hydroxy pyrimidine with phenols using DIAD and PPh3
has been demonstrated for the synthesis of 2-aryloxy pyrimidine.
The synthesis of heteroaryl ethers of these cyclic amides is
generally achieved through activation at 2-position of pyrimidin-
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2014.08.079
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

P. B. Thorat et al. / Tetrahedron Letters 55 (2014) 5718–5721
5719
N
N
R2
N
R2
N
R1
R
N
R1
R
N
N
N
N
DBU
PF6
N
N
N
O
P
activation at
2-position
O
OH
N
N
N
Cs2CO3, H2O2 (0.8%)
DME, 10 h, RT
ArB(OH)2, Pd(PPh3)4
C-O cross-coupling
PyAOP
R2
N
R2
N
R2
R2
ArOH
activation at
2-position
R1
R
R1
R1
R
R1
R
DIAD, Ph3P
ArOH
SNAr
N
N
N
Mitsunobu
R
POCl3 or TsCl
N
Z
OH
N
H
O
coupling
N
OAr
Z = Cl, OTs
Scheme 1. Literature methods of 2-aryloxy pyrimidine synthesis.
symmetrical diaryliodonium salts to afford 2-aryloxy pyrimidine
derivatives under metal-free conditions (Scheme 2).
R1
N
O
R1
O
OTf
K2CO3 (2 equiv)
I
R
N
R
N
The requisite 4-aryl-6-methyl-pyrimidine-2(1H)-ones 1 were
obtained by the oxidative dehydrogenation of Biginelli 3,4-dihy-
dropyrimidone using the literature methods.19 Similarly, the sym-
metrical diaryliodonium salts 2 (R2 = H, Br, Cl, and CH3) were
prepared using the Olofsson method.20 The O-arylation of 4-phe-
nyl-6-methyl-pyrimidine-2(1H)-one 1a using diphenyliodonium
salts was chosen as a model reaction (Table 1). Among the solvents
tested, acetonitrile and toluene gave satisfactory yields of O-aryla-
tion products while DMF, THF, and 1,4-dioxane were found to be
inferior (entries 1–5). The O-arylation reaction did not proceed in
the absence of base (entry 6). Other bases such as NaOH and
Et3N were found to be less efficient compared to K2CO3 (entries 7
and 8). The O-arylation of 1a using diphenyliodonium tetrafluoro-
borates and chlorides was not significant compared to diphenyli-
odonium triflates (entries 9 and 10). Thus, the combination of
diphenyliodonium triflate with K2CO3 as the base in toluene was
found to be the most suitable for O-arylation of 1a. Therefore, we
gradually changed the quantity of 2 and K2CO3 in subsequent opti-
mization studies which revealed that the formation of 3a took
place in all the cases (entries 11–14). However, the maximum yield
toluene, reflux, 8-10 h
N
H
1
O
R2
O
R2
R2
metal-free
ligand-free
3
2
Scheme 2. O-Arylation of 4-aryl-6-methyl-pyrimidine-2(1H)-one derivatives using
diaryliodonium salts.
However, this strategy is mainly successful with phenols bearing
electron withdrawing groups.11
Diaryliodonium salts are an important class of hypervalent
iodine compounds.12 They have received renewed interest in
organic synthesis as more reactive version of iodoarenes for vari-
ous C–C, C–O, C–N, and C–S cross-coupling reactions. They have
emerged as a source of aryl cation in the O-arylation of phenols,13
carboxylic acids,14 alcohols,15 vicinal diols,16 and N-hydroxyph-
thalimide.17 The cyclic amides are in tautomerism with 2-hydroxy
pyrimidine or pyridine and therefore, we were intrigued with the
possibility of C–O cross-coupling reaction with diaryliodonium
salts. Herein, we report the direct C–O cross-coupling reactions
of 4-aryl-6-methyl-pyrimidine-2(1H)-one derivatives using
Table 1
Optimization of O-arylation of Biginelli ethyl 6-methyl-2-oxo-4-phenyl-1,2-dihydropyrimidine-5-carboxylate 1a
X
O
O
I
Base
EtO
N
+
N
EtO
solvent
reflux
N
H
1a
O
N
O
2
3a
Entry
Ph2IOX
Base
Solvent
Time (h)
Yield of 3a (%)a
1
2
3
4
5
6
7
8
Ph2IOTf (1.0 equiv)
Ph2IOTf (1.0 equiv)
Ph2IOTf (1.0 equiv)
Ph2IOTf (1.0 equiv)
Ph2IOTf (1.0 equiv)
Ph2IOTf (1.0 equiv)
Ph2IOTf (1.5 equiv)
Ph2IOTf (1.5 equiv)
Ph2IBF4 (1.5 equiv)
Ph2ICl (1.5 equiv)
Ph2IOTf (1.0 equiv)
Ph2IOTf (1.0 equiv)
Ph2IOTf (1.2 equiv)
Ph2IOTf (1.5 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
—
NaOH (2.0 equiv)
Et3N (2.0 equiv)
K2CO3 (2.0 equiv)
K2CO3 (2.0 equiv)
K2CO3 (1.2 equiv)
K2CO3 (1.5 equiv)
K2CO3 (1.5 equiv)
K2CO3 (2.0 equiv)
DMF
THF
Dioxane
CH3CN
24
24
24
24
24
24
24
24
24
24
24
24
15
10
12
17
23
39
43
0
14
49
46
52
49
52
60
65
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
9
10
11
12
13
14
a
Isolated yields.

5720
P. B. Thorat et al. / Tetrahedron Letters 55 (2014) 5718–5721
Table 2
Synthesis of 2-aryloxy pyrimidine derivatives using diaryliodonium triflatesa
R1
N
O
R1
O
OTf
R2
K2CO3 (2 equiv)
toluene, reflux,
I
R
N
R
N
R2
O
R2
Me
O
3a-p
N
H
8-10 h
2
1
OMe
O
O
O
EtO
N
EtO
N
EtO
EtO
N
N
3a
O
N
O
N
O
(65%)
3c
3b
(53%)
(74%)
F
Cl
OMe
O
O
O
O
N
EtO
N
EtO
EtO
N
N
N
O
N
O
O
3f
(62%)
3e (72%)
3d
(72%)
Cl
NO2
O
O
Cl
H3C
N
EtO
N
N
N
O
N
O
N
O
3h (64%)
3g
(61%)
OMe
3i (60%)
Me
OMe
O
O
O
O
Cl
Br
Br
Br
Br
H3C
N
EtO
EtO
N
N
EtO
EtO
N
O
N
O
N
3l
O
3j
(63%)
F
3k (58%)
(65%)
F
NO2
O
O
N
Br
EtO
N
N
N
O
N
O
N
O
3m
(63%)
3n
(65%)
3o
(62%)
Cl
O
CH3
EtO
N
N
O
3p
(55%)
a
Reaction conditions: 4-aryl-6-methyl-pyrimidine-2(1H)-one derivatives (2 mmol), diaryliodonium triflate (3 mmol), and
K2CO3 (4 mmol) in 10 mL toluene under reflux for 8–10 h.

P. B. Thorat et al. / Tetrahedron Letters 55 (2014) 5718–5721
5721
46, 2290; (c) Quan, Z.-J.; Jing, F.-Q.; Zhang, Z.; Da, Y.-X.; Wang, X.-C. Eur. J. Org.
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of 3a (65%) was achieved using 1.5 and 2.0 equiv of diphenyliodo-
nium triflate and K2CO3, respectively.18
5. The oxidative aromatization of 3,4-dihydropyrimidine-2(1H)-one is reported
using HNO3, DDQ, Pd/C, TBHP/CuCl2, CAN/NaHCO3, Co(NO3)2/K2S2O8, K2S2O8/
ultrasound, TBHP/PhI(OAc)2, PCC, NaNO2, Ca(OCl)2, rhenium(I) complexes/
photochemical conditions, and N-hydroxyphthalimide (NHPI)/Co(OAc)2/O2.
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Under these optimized conditions, the reactions of various 4-
aryl-6-methyl-pyrimidine-2(1H)-one derivatives with four differ-
ent symmetrical diaryliodonium triflates 2 (R2 = H, CH3, Br, and
Cl) were performed (Table 2). In general, good to excellent yields
of O-arylation products were obtained in all the cases. The elec-
tron-withdrawing and donating groups present on 4-aryl substitu-
ent were tolerated under the reaction conditions. All the products
were characterized by IR, NMR (1H and 13C), and LCMS analysis
(Supplementary data).
In summary, we have developed a new method for the O-aryla-
tion of 4-aryl-6-methyl-1,2-dihydropyrimidines using diaryliodo-
nium salts under transition metal-free conditions. A wide range
of 2-aryloxy pyrimidine derivatives were obtained in good to
excellent yields. Compared with previous procedures, this method
is a direct strategy for the synthesis of 2-aryloxy pyrimidines and
avoids the activation at 2-position (chlorides, tosylates, and pyr-
idotriazol-1-yloxy) of 1,2-dihydropyrimidines.
10. (a) Wang, X.-C.; Yang, G.-J.; Jia, X.-D.; Zhang, Z.; Da, Y.-X.; Quan, Z.-J.
Tetrahedron 2011, 67, 3267; (b) Kang, F. A.; Kodah, J.; Guan, Q.; Li, X.;
Murray, W. V. J. Org. Chem. 2005, 70, 1957.
Acknowledgments
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1123; (b) Grushin, V. V. Chem. Soc. Rev. 2000, 29, 315; (c) Zhdankin, V. V.; Stang,
P. J. Chem. Rev. 2002, 102, 2523; (d) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008,
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Yusubov, M. S.; Maskaev, A. V.; Zhdankin, V. V. Arkivoc 2011, i, 370.
13. (a) Jalalian, N.; Ishikawa, E. E.; Silva, L. F., Jr.; Olofsson, B. Org. Lett. 2011, 13,
1552; (b) Jalalian, N.; Petersen, T. B.; Olofsson, B. Chem. Eur. J. 2012, 18, 14140.
14. Petersen, T. B.; Khan, R.; Olofsson, B. Org. Lett. 2011, 13, 3462.
15. Lindstedt, E.; Ghosh, R.; Olofsson, B. Org. Lett. 2013, 23, 6070.
16. Kuriyama, M.; Hamaguchi, N.; Onomura, O. Chem. Eur. J. 2012, 1591.
17. Ghosh, R.; Olofsson, B. Org. Lett. 2014, 16, 1830.
18. General experimental procedure for O-arylation of 4-aryl-6-methyl-pyrimidine-
2(1H)-one derivatives: To the stirred solution of 4-aryl-6-methyl-pyrimidine-
2(1H)-one derivatives (2 mmol) in toluene (10 mL), potassium carbonate
(4 mmol) and diaryliodonium triflate (3 mmol) were added. The mixture was
refluxed for 8–10 h. The progress of the reaction was monitored by TLC. After
the completion of reaction, toluene was evaporated under vacuum. Water was
added to the reaction mass and it was extracted with dichloromethane
(10 mL Â 3). The combined organic layers were dried over anhydrous sodium
sulfate and evaporated under reduced pressure. The crude product thus
obtained was further purified by column chromatography using petroleum
ether and ethyl acetate.
The authors are thankful to the Department of Science and
Technology, New Delhi, India (No. SR/S1/OC-72/2009) for financial
support. The authors are also grateful to the SAIF, Punjab Univer-
sity, Chandigarh, India, for recording the NMR spectra.
Supplementary data
Supplementary data (copies of 1H NMR, 13C NMR spectra, and
LCMS are provided for all the compounds synthesized) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.08.079.
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