Microwave-assisted copper-powder-catalyzed synthesis of pyrimidinones from β-bromo α,β-unsaturated carboxylic acids and amidines

Article abstract of DOI:10.1055/s-0033-1340283

β-Bromo α,β-unsaturated carboxylic acids were coupled and cyclized with amidine hydrochlorides by microwave irradiation in the presence of catalytic amounts of copper powder and a base to give the corresponding pyrimidinones in high yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340283

LETTER
▌2705
lMetteircrowave-Assisted Copper-Powder-Catalyzed Synthesis of Pyrimidinones
from β-Bromo α,β-Unsaturated Carboxylic Acids and Amidines
Copper-Powder-Catalyzed Synthesis of Pyrimidinones
Son Long Ho, Chan Sik Cho*
Department of Applied Chemistry, Kyungpook National University, Daegu 702-701, South Korea
Fax +82(53)9506594; E-mail: cscho@knu.ac.kr
Received: 30.08.2013; Accepted after revision: 05.09.2013
O
O
Abstract: β-Bromo α,β-unsaturated carboxylic acids were coupled
and cyclized with amidine hydrochlorides by microwave irradiation
in the presence of catalytic amounts of copper powder and a base to
give the corresponding pyrimidinones in high yields.
1. PBr3, DMF
HN=C(R)NH2⋅HCl (2)
NH
OH
2. NaClO2, H2O2
Cu powder, MW
N
R
O
Br
1
3
Key words: copper, coupling, cyclization, heterocycles, heteroge-
neous catalysis
Scheme 1 Synthesis of pyrimidinones from ketones
Because the pyrimidinone ring plays an important role as
a basic scaffold component in numerous biologically ac-
tive compounds, many pyrimidinone-containing com-
pounds have been synthesized and tested for biological
activity.1–7 Fu and co-workers have shown that 2-bromo-
cycloalk-1-enecarboxylic acids couple and cyclize with
amidine hydrochlorides in the presence of copper(I) io-
dide to give bicyclic pyrimidinones.8 A similar coupling
and cyclization of 2-bromocyclohex-1-enecarboxylic acid
with amidine hydrochlorides to give bicyclic pyrimidi-
nones can be induced by a magnetite (Fe3O4) nanoparticle-
supported copper(I) catalyst.9 Furthermore, 2-halobenzoic
acids couple and cyclize with amidine hydrochlorides in
the presence of copper(I) iodide or tris(acetylacetonato)-
iron(III) to give quinazolinones (benzo-fused pyrimidi-
nones).10,11
First we optimized the conditions for coupling and cycli-
zation of 2-bromocyclohex-1-enecarboxylic acid (1a)
with benzenecarboximidamide hydrochloride (2a) (Table
1).13,15 Treatment of acid 1a with two equivalents of ami-
dine 2a in N,N-dimethylformamide at 100 °C for 15 min
in the presence of a catalytic amount of copper powder
and sodium tert-butoxide under microwave irradiation
gave 2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one
(3a) in 73% isolated yield with incomplete conversion of
1a (Table 1, entry 1).16 The yield of 3a increases on pro-
longing the reaction time to 30 min, and conversion of 1a
was complete (entry 2);17 the conversion of 1a was not
monitored until after it had disappeared on the thin-layer
chromatogram. Increasing the initial microwave power to
150 or 200 W did not change the yield of 3a (entry 3). The
reaction did not proceed at all in the absence of copper
powder (entry 4). Lowering the reaction temperature re-
sulted in smaller yields of 3a (entries 5 and 6). The reac-
tion also proceeded in the presence of various other bases,
such as cesium carbonate, potassium carbonate, or tripo-
tassium phosphate, but the yields of 3a were generally
lower than that obtained in the presence of sodium tert-
butoxide (entries 2, 7–9). Among the solvents examined,
N,N-dimethylformamide was found to be that of choice
(entries 2, 10, and 11). When used with sodium tert-but-
oxide and N,N-dimethylformamide, copper(I) salts such
as copper(I) chloride, iodide, or acetate showed slightly
lower catalytic activities than did copper powder (entries
2, 12–15). The best results in terms of the yield of product
3a and complete conversion of 1a were therefore achieved
by the using the set of reaction conditions shown in entry
2 of Table 1.
As part of our continuing studies on transition metal-cata-
lyzed cyclization reactions of β-bromo α,β-unsaturated al-
dehydes and their derivatives, we have identified several
new methods for the synthesis of carbocyclic and hetero-
cyclic compounds.12 β-Bromo α,β-unsaturated aldehydes
and their derivatives are readily prepared from α-meth-
ylene group-containing ketones by bromination under
Vilsmeier–Haak conditions,13 with subsequent transfor-
mation, and the products can serve as valuable building
blocks for the construction of various cyclic compounds
(Scheme 1).14 In developing a coupling and cyclization
protocol for the synthesis of pyrimidinones, we attempted
to identify a method that would combine catalysis with
microwave irradiation. This report describes an efficient
and rapid protocol for the synthesis of pyrimidinones by
copper-powder-catalyzed coupling and cyclization of β-
bromo α,β-unsaturated carboxylic acids with amidine hy-
drochlorides under microwave irradiation (Scheme 1).
Having optimized the reaction conditions, we subjected
various β-bromo α,β-unsaturated carboxylic acids 1 to re-
action with amidine hydrochlorides 2 to investigate the
scope of the reaction; several representative results are
summarized in Table 2.13,15,18 The coupling and cycliza-
tion of 1a with ethanimidamide hydrochloride (2b) gave
the corresponding pyrimidinone 3b in good yield. The
six-membered β-bromo α,β-unsaturated carboxylic acids
SYNLETT 2013, 24, 2705–2708
Advanced online publication: 05.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340283; Art ID: ST-2013-U0835-L
© Georg Thieme Verlag Stuttgart · New York

2706
S. L. Ho, C. S. Cho
LETTER
1b and 1c reacted with amidine 2a to give the correspond- sizing the pyrimidinone scaffold from readily available
ing pyrimidinones 3c and 3d in similar yields, irrespective ketones. Further studies on syntheses of heterocycles by
of the presence of the methyl and phenyl substituents on using the copper-powder–microwave irradiation system
1b and 1c. Cyclic β-bromo α,β-unsaturated carboxylic ac- are underway.
ids of various ring sizes 1d–g similarly gave the corre-
sponding pyrimidinones 3e–h in yields of 61–92%, the
highest yield being obtained from the seven-membered β-
bromo α,β-unsaturated carboxylic acid 1e. We also exam-
ined the reactions of the β-bromo α,β-unsaturated carbox-
ylic acids 1h and 1i to test the effects on the reaction of the
positions of the bromide and carboxy groups. Both 1h and
1i underwent coupling and cyclization reactions, but the
product yields were generally lower than those obtained
from the β-bromo α,β-unsaturated carboxylic acids 1a–f.
Table 2 Copper-Powder-Catalyzed Synthesis of Pyrimidinones 3
from β-Bromo α,β-Unsaturated Carboxylic Acids 1 and Amidines 2
under Microwave Irradiation
O
O
Cu powder
HN
NH2
•HCl
NH
OH
+
NaOt-Bu, DMF,
100 °C, 30 min
R
N
R
Br
1
2a R = Ph
2b R = Me
3
Acida
Amidine Product
Yield
(%)
Table 1 Optimization of the Conditions for the Reaction of Carbox-
ylic Acid 1a with Amidine 2a
O
O
N
O
COOH
OH
Cu catalyst
MW
NH
HN
NH2
•HCl
NH
2a
89
+
Br
R
Br
Ph
N
Ph
1a
2a
3a
1a
3a
Entrya Cu catalyst
Base
Solvent
Yield (%)
2b
2a
3b
71
86
O
O
N
1b
2
Cu powder
Cu powder
Cu powder
–
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
Cs2CO3
DMF
73
89
89
–
OH
NH
DMF
Br
Ph
3c
4
DMF
1b
3c
DMF
O
O
N
5d
6e
7
Cu powder
Cu powder
Cu powder
Cu powder
Cu powder
Cu powder
Cu powder
CuCl
DMF
–
Ph
Ph
OH
NH
2a
2a
2a
2a
83
75
92
85
DMF
64
80
76
70
80
71
70
75
81
73
Br
Ph
DMF
1c
3d
3e
3f
O
O
8
K2CO3
DMF
OH
NH
9
K3PO4
DMF
10
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
1,4-dioxane
toluene
DMF
Br
N
Ph
1d
1e
1f
11
12
13
14
15
O
O
N
OH
NH
CuBr
DMF
Br
O
Ph
CuI
DMF
CuOAc
DMF
O
a Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), copper catalyst
(0.05 mmol), base (2 mmol), solvent (3 mL), 100 °C, 30 min, micro-
OH
NH
wave irradiation (100 W initial power), unless otherwise stated.
Br
N
Ph
b 15 min.
c 150 W or 200 W initial power
3g
d 25 °C.
e 50 °C.
O
O
N
OH
NH
2a
61
Br
Ph
In summary, we have demonstrated that β-bromo α,β-un-
saturated carboxylic acids react with amidine hydrochlo-
rides in the presence of copper powder under microwave
irradiation to give the corresponding pyrimidinones. The
reaction provides a new and efficient method for synthe-
1g
3h
Synlett 2013, 24, 2705–2708
© Georg Thieme Verlag Stuttgart · New York

LETTER
Copper-Powder-Catalyzed Synthesis of Pyrimidinones
2707
Table 2 Copper-Powder-Catalyzed Synthesis of Pyrimidinones 3
from β-Bromo α,β-Unsaturated Carboxylic Acids 1 and Amidines 2
under Microwave Irradiation (continued)
(8) Guo, Q.; Yang, H.; Liu, H.; Jiang, Y.; Fu, H. Synlett 2010,
2611.
(9) Yu, L.; Wang, M.; Li, P.; Wang, L. Appl. Organomet. Chem.
2012, 26, 576.
(10) (a) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem. Int.
Ed. 2009, 48, 348. (b) Zhang, X.; Ye, D.; Sun, H.; Guo, D.;
Wang, J.; Huang, H.; Zhang, X.; Jiang, H.; Liu, H. Green
Chem. 2009, 11, 1881.
(11) It has also been reported that quinazolinones can be
synthesized by CuI-catalyzed coupling of 2-iodobenzamides
with methanimidamide acetate followed by condensative
cyclization; see: Zhou, J.; Fu, L.; Lv, M.; Liu, J.; Pei, D.;
Ding, K. Synthesis 2008, 3974.
O
O
Cu powder
HN
NH2
•HCl
NH
OH
+
NaOt-Bu, DMF,
100 °C, 30 min
R
N
R
Br
1
2a R = Ph
2b R = Me
3
Acida
Amidine Product
Yield
(%)
(12) (a) Cho, C. S.; Patel, D. B.; Shim, S. C. Tetrahedron 2005,
61, 9490. (b) Cho, C. S.; Shim, H. S. Tetrahedron Lett. 2006,
47, 3835. (c) Cho, C. S.; Patel, D. B. Tetrahedron 2006, 62,
6388. (d) Cho, C. S.; Kim, J. U.; Choi, H.-J. J. Organomet.
Chem. 2008, 693, 3677. (e) Cho, C. S.; Kim, H. B.; Lee, S.
Y. J. Organomet. Chem. 2010, 695, 1744. (f) Cho, C. S.;
Kim, H. B. Catal. Lett. 2010, 140, 116. (g) Cho, C. S.; Kim,
H. B. J. Organomet. Chem. 2011, 696, 3264. (h) Lee, H. K.;
Cho, C. S. Appl. Organomet. Chem. 2012, 26, 185. (i) Lee,
H. K.; Cho, C. S. Appl. Organomet. Chem. 2012, 26, 406.
(j) Cho, C. S.; Son, J. I.; Yoon, N. S. Appl. Organomet.
Chem. 2012, 26, 499. (k) Lee, H. K.; Cho, C. S. Appl.
Organomet. Chem. 2012, 26, 570. (l) Ho, S. L.; Cho, C. S.;
Choi, H.-J.; Sohn, H.-S. Appl. Organomet. Chem. 2013, 27,
277. (m) Son, J.-K.; Cho, C. S.; Choi, H.-J. Appl.
Organomet. Chem. 2013, 27, 380. (n) Bae, Y. K.; Cho, C. S.
Synlett 2013, 24, 1848.
O
N
O
NH
OH
2a
65
Ph
Br
1h
1i
3i
O
O
N
OH
NH
2a
58
Br
Ph
3j
a Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), Cu powder (0.05
mmol), t-BuONa (2 mmol), DMF (3 mL), 100 °C, 30 min, microwave
irradiation (100 W initial power).
(13) (a) Arnold, Z.; Holly, A. Collect. Czech. Chem. Commun.
1961, 26, 3059. (b) Coates, R. M.; Senter, P. D.; Baker, W.
R. J. Org. Chem. 1982, 47, 3597.
Acknowledgment
(14) (a) Brahma, S.; Ray, J. K. Tetrahedron 2008, 64, 2883.
(b) Jana, R.; Chatterjee, I.; Samanta, S.; Ray, J. K. Org. Lett.
2008, 10, 4795. (c) Karthikeyan, P.; Meena Rani, A.;
Saiganesh, R.; Balasubramanian, K. K.; Kabilan, S.
Tetrahedron 2009, 65, 811. (d) Samanta, S.; Jana, R.; Ray,
J. K. Tetrahedron Lett. 2009, 50, 6751. (e) Nandi, S.; Ray, J.
K. Tetrahedron Lett. 2009, 50, 6993. (f) Jana, R.; Paul, S.;
Biswas, A.; Ray, J. K. Tetrahedron Lett. 2010, 51, 273.
(g) Samanta, S.; Yasmin, N.; Kundu, D.; Ray, J. K.
Tetrahedron Lett. 2010, 51, 4132. (h) Yasmin, N.; Ray, J. K.
Synlett 2010, 924. (i) Paul, S.; Gorai, T.; Koley, A.; Ray, J.
K. Tetrahedron Lett. 2011, 52, 4051.
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF),
funded by the Ministry of Education, Science and Technology
(2010-0007563), and by Kyungpook National University Research
Fund, 2013.
References and Notes
(1) Driscoll, J. S.; Marquez, V. E.; Plowman, J.; Liu, P. S.;
Kelley, J. A.; Barchi, J. J. Jr. J. Med. Chem. 1991, 34, 3280.
(2) Salimbeni, A.; Canevotti, R.; Paleari, F.; Poma, D.; Caliari,
S.; Fici, F.; Cirillo, R.; Renzetti, A. R.; Subissi, A.; Belvisi,
L.; Bravi, G.; Scolastico, C.; Giachetti, A. J. Med. Chem.
1995, 38, 4806.
(15) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567.
(16) The reaction appears to proceed by an initial Cu-catalyzed
C–N coupling between 1a and 2a followed by condensative
cyclization.
(3) Saladino, R.; Crestini, C.; Palamara, A. T.; Danti, M. C.;
Manetti, F.; Corelli, F.; Garaci, E.; Botta, M. J. Med. Chem.
2001, 44, 4554.
(17) The reaction did not proceed efficiently under normal
heating (100 °C, 3 h), 3a being obtained in only 14% yield.
(18) Pyrimidinones 3; General Procedure
(4) Madhavan, G. R.; Chakrabarti, R.; Vikramadithyan, R. K.;
Mamidi, R. N. V. S.; Balraju, V.; Rajesh, B. M.; Misra, P.;
Kumar, S. K. B.; Lohray, B. B.; Lohray, V. B.; Rajagopalan,
R. Bioorg. Med. Chem. 2002, 10, 2671.
(5) Saleh, M. A.; Abdel-Megeed, M. F.; Abdo, M. A.; Shokr, A.
M. Molecules 2003, 8, 363.
(6) Petricci, E.; Mugnaini, C.; Radi, M.; Togninelli, A.;
Bernardini, C.; Manetti, F.; Parlato, M. C.; Renzulli, M. L.;
Alongi, M.; Falciani, C.; Corelli, F.; Botta, M. ARKIVOC
2006, (vii), 452.
(7) Mai, A.; Artico, M.; Rotili, D.; Tarantino, D.; Clotet-Codina,
I.; Armand-Ugón, M.; Ragno, R.; Simeoni, S.; Sbardella, G.;
Nawrozkij, M. B.; Samuele, A.; Maga, G.; Esté, J. A. J. Med.
Chem. 2007, 50, 5412.
A 10 mL microwave reaction tube was charged with the
appropriate β-bromo α,β-unsaturated carboxylic acid 1 (0.5
mmol) and amidine hydrochloride 2 (1 mmol), together with
Cu powder (0.05 mmol), t-BuONa (2 mmol), and DMF (3
mL). The mixture was heated to 100 °C for 30 min by
microwave irradiation (CEM Discover Microwave System)
at 100 W initial power. The mixture was then cooled to r.t.
and filtered through a short column of silica gel (CHCl3–
MeOH) to remove inorganic salts. Evaporation of the
solvent gave a crude mixture that was purified by TLC
[silica gel 60 GF254 (Merck), CHCl3–MeOH].
6-Methyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-
one (3c)
White solid; yield: 103 mg (86%); mp 254–256 °C. IR
(KBr): 1638 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ =
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2705–2708

2708
S. L. Ho, C. S. Cho
LETTER
1.12 (d, J = 6.6 Hz, 3 H), 1.41–1.51 (m, 1 H), 1.83–1.95 (m,
2 H), 2.05–2.12 (m, 1 H), 2.71–2.84 (m, 3 H), 7.44–7.54 (m,
3 H), 8.19–8.21 (m, 2 H), 12.88 (br s, 1 H). 13C NMR (100
MHz, CDCl3): δ = 21.73, 28.25, 30.31, 30.63, 32.03, 119.91,
127.66, 129.02, 131.58, 132.65, 153.45, 162.47, 164.95.
HRMS (EI): m/z [M+] calcd for C15H16N2O: 240.1263;
found: 240.1260. Anal. Calcd for C15H16N2O: C, 74.97; H,
6.71; N, 11.66. Found: C, 74.70; H, 6.72; N, 11.83.
2,6-Diphenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one
(3d)
White solid; yield: 95 mg (61%); mp 223–224 °C. IR (KBr):
1622 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.25–
1.53 (m, 12 H), 1.80–1.92 (m, 4 H), 2.68–2.70 (m, 4 H),
7.44–7.54 (m, 3 H), 8.16–8.18 (m, 2 H), 12.01 (br s, 1 H). 13C
NMR (100 MHz, CDCl3): δ = 22.02, 22.87, 23.16, 23.88,
25.25, 25.47, 25.86, 25.99, 28.93, 31.13, 123.11, 127.21,
128.74, 131.38, 132.47, 153.69, 164.61, 165.18. HRMS
(EI): m/z [M+] calcd for C20H26N2O: 310.2045; found:
310.2045. Anal. Calcd for C20H26N2O: C, 77.38; H, 8.44; N,
9.02. Found: C, 77.19; H, 8.48; N, 9.02.
White solid; yield: 125 mg (83%); mp 223–225 °C. IR
(KBr): 1629 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.94–2.05 (m, 1 H), 2.18–2.22 (m, 1 H), 2.59–2.66 (m, 1 H),
2.89–3.10 (m, 4 H), 7.24–7.38 (m, 5 H), 7.45–7.52 (m, 3 H),
8.13–8.16 (m, 2 H), 12.18 (br s, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 29.79, 32.55, 39.55, 120.02, 126.63, 127.10,
127.46, 128.77, 129.21, 131.81, 132.53, 145.74, 153.55,
162.19, 164.36. HRMS (EI): m/z [M+] calcd for C20H18N2O:
302.1419; found: 302.1416. Anal. Calcd for C20H18N2O: C,
79.44; H, 6.00; N, 9.26. Found: C, 79.12; H, 5.82; N, 9.20.
2-Phenyl-3,5,6,7-tetrahydro-4H-
2-Phenyl-5,6-dihydrobenzo[h]quinazolin-4(3H)-one (3i)
White solid; yield: 89 mg (65%); mp 229–230 °C. IR (KBr):
1638 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.98–
3.00 (m, 4 H), 7.26–7.29 (m, 1 H), 7.36–7.41 (m, 2 H), 7.55–
7.59 (m, 3 H), 8.32–8.41 (m, 3 H), 12.20 (br s, 1 H). 13
C
NMR (100 MHz, DMSO-d6): δ = 26.91, 28.98, 125.73,
126.84, 127.28, 127.84, 128.82, 130.53, 131.62, 132.40,
132.58, 138.71, 155.94, 157.06, 164.10. HRMS (EI): m/z
[M+] calcd for C18H14N2O: 274.1106; found: 274.1108.
Anal. Calcd for C18H14N2O: C, 78.81; H, 5.14; N, 10.21.
Found: C, 78.72; H, 5.01; N, 10.02.
cyclopenta[d]pyrimidin-4-one (3e)
3-Phenyl-5,6-dihydrobenzo[f]quinazolin-1(2H)-one (3j)
White solid; yield: 80 mg (58%); mp 226–228 °C. IR (KBr):
1625 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.01 (s,
4 H), 7.26–7.30 (m, 1 H), 7.33–7.37 (m, 1 H), 7.56–7.63 (m,
4 H), 8.32–8.34 (m, 2 H), 8.79 (d, J = 7.6 Hz, 1 H), 12.63 (br
s, 1 H). 13C NMR (100 MHz, DMSO-d6): δ = 27.85, 31.30,
126.58, 126.80, 127.04, 127.41, 127.52, 127.83, 128.58,
129.06, 130.24, 132.02, 135.84, 154.97, 161.96, 164.49.
HRMS (EI): m/z [M+] calcd for C18H14N2O: 274.1106;
found: 274.1104. Anal. Calcd for C18H14N2O: C, 78.81; H,
5.14; N, 10.21. Found: C, 78.61; H, 5.47; N, 10.31.
White solid; yield: 80 mg (75%); mp 212–214 °C. IR (KBr):
1650 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.10–
2.18 (m, 2 H), 2.87–3.00 (m, 3 H), 7.44–7.57 (m, 3 H), 8.10–
8.12 (m, 2 H), 11.92 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 20.71, 27.06, 34.33,
127.45, 127.62, 128.19, 128.60, 131.32, 156.73, 161.07,
167.88. HRMS (EI): m/z [M+] calcd for C13H12N2O:
212.0950; found: 212.0952. Anal. Calcd for C13H12N2O: C,
73.56; H, 5.70; N, 13.20. Found: C, 73.45; H, 5.65; N, 13.11.
2-Phenyl-5,6,7,8,9,10,11,12,13,14-
decahydrocyclododeca[d]pyrimidin-4(3H)-one (3h)
Synlett 2013, 24, 2705–2708
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